RBCC

Full text data of C19orf12

C19orf12 [Confidence: low (only semi-automatic identification from reviews)]
Protein C19orf12

UniProt Q9NSK7
ID CS012_HUMAN Reviewed; 152 AA.
AC Q9NSK7; B3KQ16; Q0D2Q0; Q6P4C5; Q9BSL7;
DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-JAN-2012, sequence version 3.
DT 22-JAN-2014, entry version 71.
DE RecName: Full=Protein C19orf12;
GN Name=C19orf12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND NUCLEOTIDE
RP SEQUENCE [LARGE SCALE MRNA] OF 1-144 (ISOFORM 4).
RC TISSUE=Stomach, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3), AND
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 72-152 (ISOFORMS 1/4).
RC TISSUE=Brain, Lymph, and Ovary;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 34-141 (ISOFORMS 1/2).
RC TISSUE=Melanoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [5]
RP VARIANTS NBIA4 MET-11; ARG-53; GLU-65 AND ARG-69, VARIANTS GLU-142 AND
RP THR-142, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=21981780; DOI=10.1016/j.ajhg.2011.09.007;
RA Hartig M.B., Iuso A., Haack T., Kmiec T., Jurkiewicz E., Heim K.,
RA Roeber S., Tarabin V., Dusi S., Krajewska-Walasek M., Jozwiak S.,
RA Hempel M., Winkelmann J., Elstner M., Oexle K., Klopstock T.,
RA Mueller-Felber W., Gasser T., Trenkwalder C., Tiranti V.,
RA Kretzschmar H., Schmitz G., Strom T.M., Meitinger T., Prokisch H.;
RT "Absence of an orphan mitochondrial protein, c19orf12, causes a
RT distinct clinical subtype of neurodegeneration with brain iron
RT accumulation.";
RL Am. J. Hum. Genet. 89:543-550(2011).
RN [6]
RP VARIANT NBIA4 GLN-121.
RX PubMed=22508347; DOI=10.1002/mds.24980;
RA Horvath R., Holinski-Feder E., Neeve V.C., Pyle A., Griffin H.,
RA Ashok D., Foley C., Hudson G., Rautenstrauss B., Nurnberg G.,
RA Nurnberg P., Kortler J., Neitzel B., Bassmann I., Rahman T.,
RA Keavney B., Loughlin J., Hambleton S., Schoser B., Lochmuller H.,
RA Santibanez-Koref M., Chinnery P.F.;
RT "A new phenotype of brain iron accumulation with dystonia, optic
RT atrophy, and peripheral neuropathy.";
RL Mov. Disord. 27:789-793(2012).
RN [7]
RP VARIANTS NBIA4 PHE-39; PRO-48; ARG-53; LEU-60; GLU-65; VAL-65; ARG-69;
RP LEU-83; SER-98 AND PRO-134, AND VARIANTS GLU-142; THR-142 AND ARG-149.
RX PubMed=23269600; DOI=10.1212/WNL.0b013e31827e07be;
RA Hogarth P., Gregory A., Kruer M.C., Sanford L., Wagoner W.,
RA Natowicz M.R., Egel R.T., Subramony S.H., Goldman J.G.,
RA Berry-Kravis E., Foulds N.C., Hammans S.R., Desguerre I.,
RA Rodriguez D., Wilson C., Diedrich A., Green S., Tran H., Reese L.,
RA Woltjer R.L., Hayflick S.J.;
RT "New NBIA subtype: genetic, clinical, pathologic, and radiographic
RT features of MPAN.";
RL Neurology 80:268-275(2013).
CC -!- SUBCELLULAR LOCATION: Mitochondrion. Mitochondrion membrane;
CC Single-pass membrane protein (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=4;
CC IsoId=Q9NSK7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NSK7-2; Sequence=VSP_027227;
CC Name=3;
CC IsoId=Q9NSK7-3; Sequence=VSP_037995, VSP_027228;
CC Name=1;
CC IsoId=Q9NSK7-4; Sequence=VSP_037995;
CC -!- INDUCTION: Up-regulated during adipocyte differentiation in an in
CC vitro preadipocyte differentiation model.
CC -!- DISEASE: Neurodegeneration with brain iron accumulation 4 (NBIA4)
CC [MIM:614298]: A neurodegenerative disorder associated with iron
CC accumulation in the brain, primarily in the basal ganglia. NBIA4
CC results in speech difficulty, extrapyramidal signs, oromandibular
CC and generalized dystonia, and parkinsonism. Most patients have
CC progressive involvement of the corticospinal tract, with
CC spasticity, hyperreflexia, and extensor plantar responses.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
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DR EMBL; AK057185; BAG51878.1; -; mRNA.
DR EMBL; DA708831; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; AC010513; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004957; AAH04957.1; -; mRNA.
DR EMBL; BC009946; AAH09946.1; -; mRNA.
DR EMBL; BC063518; AAH63518.1; -; mRNA.
DR EMBL; BC017211; AAH17211.2; -; mRNA.
DR EMBL; AL162066; CAB82403.1; -; mRNA.
DR PIR; T47169; T47169.
DR RefSeq; NP_001026896.2; NM_001031726.3.
DR RefSeq; NP_001242975.1; NM_001256046.1.
DR RefSeq; NP_001242976.1; NM_001256047.1.
DR RefSeq; NP_001269858.1; NM_001282929.1.
DR RefSeq; NP_001269859.1; NM_001282930.1.
DR RefSeq; NP_001269860.1; NM_001282931.1.
DR RefSeq; NP_113636.2; NM_031448.4.
DR UniGene; Hs.529094; -.
DR ProteinModelPortal; Q9NSK7; -.
DR IntAct; Q9NSK7; 2.
DR PhosphoSite; Q9NSK7; -.
DR DMDM; 156631008; -.
DR PaxDb; Q9NSK7; -.
DR PRIDE; Q9NSK7; -.
DR Ensembl; ENST00000323670; ENSP00000313332; ENSG00000131943.
DR Ensembl; ENST00000392276; ENSP00000376102; ENSG00000131943.
DR Ensembl; ENST00000392278; ENSP00000376103; ENSG00000131943.
DR Ensembl; ENST00000592153; ENSP00000467117; ENSG00000131943.
DR GeneID; 83636; -.
DR KEGG; hsa:83636; -.
DR UCSC; uc002nsj.3; human.
DR CTD; 83636; -.
DR GeneCards; GC19M030189; -.
DR H-InvDB; HIX0014979; -.
DR HGNC; HGNC:25443; C19orf12.
DR HPA; HPA046930; -.
DR MIM; 614297; gene.
DR MIM; 614298; phenotype.
DR neXtProt; NX_Q9NSK7; -.
DR Orphanet; 289560; Neurodegeneration with brain iron accumulation due to C19orf12 mutation.
DR PharmGKB; PA134981038; -.
DR eggNOG; NOG69864; -.
DR HOGENOM; HOG000007731; -.
DR HOVERGEN; HBG054390; -.
DR InParanoid; Q9NSK7; -.
DR OMA; MPIDTRE; -.
DR OrthoDB; EOG779P1P; -.
DR GenomeRNAi; 83636; -.
DR NextBio; 72567; -.
DR ArrayExpress; Q9NSK7; -.
DR Bgee; Q9NSK7; -.
DR CleanEx; HS_C19orf12; -.
DR Genevestigator; Q9NSK7; -.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0031966; C:mitochondrial membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
PE 1: Evidence at protein level;
KW Alternative splicing; Complete proteome; Disease mutation; Membrane;
KW Mitochondrion; Neurodegeneration; Polymorphism; Reference proteome;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1 152 Protein C19orf12.
FT /FTId=PRO_0000296662.
FT TRANSMEM 51 71 Helical; (Potential).
FT VAR_SEQ 1 75 Missing (in isoform 2).
FT /FTId=VSP_027227.
FT VAR_SEQ 1 11 Missing (in isoform 1 and isoform 3).
FT /FTId=VSP_037995.
FT VAR_SEQ 109 152 HLEWTDAVQLTALVMGSEALQQQLLAMLVNYVTKELRAEIQ
FT YDD -> PCSSSCWPCW (in isoform 3).
FT /FTId=VSP_027228.
FT VARIANT 11 11 T -> M (in NBIA4).
FT /FTId=VAR_066617.
FT VARIANT 39 39 S -> F (in NBIA4).
FT /FTId=VAR_069756.
FT VARIANT 48 48 A -> P (in NBIA4).
FT /FTId=VAR_069757.
FT VARIANT 53 53 G -> R (in NBIA4; dbSNP:rs200133991).
FT /FTId=VAR_066618.
FT VARIANT 60 60 P -> L (in NBIA4).
FT /FTId=VAR_069758.
FT VARIANT 65 65 G -> E (in NBIA4).
FT /FTId=VAR_066619.
FT VARIANT 65 65 G -> V (in NBIA4).
FT /FTId=VAR_069759.
FT VARIANT 69 69 G -> R (in NBIA4).
FT /FTId=VAR_066620.
FT VARIANT 83 83 P -> L (in NBIA4; dbSNP:rs201987973).
FT /FTId=VAR_069760.
FT VARIANT 98 98 R -> S (in NBIA4).
FT /FTId=VAR_069761.
FT VARIANT 121 121 L -> Q (in NBIA4).
FT /FTId=VAR_069762.
FT VARIANT 134 134 A -> P (in NBIA4; unknown pathological
FT significance).
FT /FTId=VAR_069763.
FT VARIANT 142 142 K -> E (found in families with
FT neurodegeneration with brain iron
FT accumulation; uncertain pathological
FT significance; dbSNP:rs146170087).
FT /FTId=VAR_066621.
FT VARIANT 142 142 K -> T (in dbSNP:rs79915936).
FT /FTId=VAR_066622.
FT VARIANT 149 149 Q -> R (in dbSNP:rs73023451).
FT /FTId=VAR_069764.
SQ SEQUENCE 152 AA; 16286 MW; F8C1300487F99BD5 CRC64;
MERLKSHKPA TMTIMVEDIM KLLCSLSGER KMKAAVKHSG KGALVTGAMA FVGGLVGGPP
GLAVGGAVGG LLGAWMTSGQ FKPVPQILME LPPAEQQRLF NEAAAIIRHL EWTDAVQLTA
LVMGSEALQQ QLLAMLVNYV TKELRAEIQY DD
//

MIM 614297
*RECORD*
*FIELD* NO
614297
*FIELD* TI
*614297 CHROMOSOME 19 OPEN READING FRAME 12; C19ORF12
*FIELD* TX

CLONING

By searching for genes in a region of chromosome 19 linked to
read moreneurodegeneration with brain iron accumulation (NBIA4; 614298), followed
by RT-PCR of fibroblasts and blood, Hartig et al. (2011) cloned 2 splice
variants of C19ORF12. The transcripts differ in their first exons, and
the deduced 152- and 141-amino acid proteins differ only at their N
termini. Both proteins contain a central transmembrane domain. Orthologs
of the long isoform were detected in chimpanzee and chicken only, but
close orthologs of the short isoform were detected in diverse animal
species. Endogenous or fluorescence-tagged C19ORF12 protein localized to
mitochondria. Hartig et al. (2011) stated that C19ORF12 is ubiquitously
expressed.

Landoure et al. (2013) found that the C19ORF12 protein had a complex
intracellular localization to the mitochondria or endoplasmic reticulum
(ER) when expressed in cultured COS-7 cells.

GENE FUNCTION

Hartig et al. (2011) found that expression of C19ORF12 increased with
differentiation in adipocytes along with genes involved in valine,
leucine, and isoleucine degradation and fatty acid metabolism.

GENE STRUCTURE

Hartig et al. (2011) determined that the C19ORF12 gene spans 17 kb and
contains 4 exons, including 2 alternative first exons.

MAPPING

By genomic sequence analysis, Hartig et al. (2011) mapped the C19ORF12
gene to chromosome 19q12.

MOLECULAR GENETICS

In 24 Polish patients with NBIA4 (614298), Hartig et al. (2011)
identified homozygous or compound heterozygous mutations in the C19ORF12
gene (see, e.g., 614297.0001-614297.0004). Eighteen patients carried the
same 11-bp deletion (614297.0001), and haplotype analysis indicated a
founder effect. The mutation was initially found after genomewide
linkage analysis of an affected family. Two unrelated patients who were
compound heterozygous for 2 missense mutations (614297.0003 and
614297.0004) had a milder phenotype. One had only impairment of fine
motor skills at age 19 years, and the other presented in his forties
with parkinsonism and dystonia. Hartig et al. (2011) suggested the
designation 'mitochondrial membrane protein associated neurodegeneration
(MPAN)' for this disorder.

In 23 of 161 individuals with NBIA, Hogarth et al. (2013) identified
pathogenic mutations in the C19ORF12 gene. Seventeen patients from 16
families had biallelic mutations, whereas 6 patients from 4 families had
heterozygous mutations; however, the authors considered a second occult
deleterious mutation likely to be present in these patients. The 11-bp
deletion (614297.0001) identified by Hartig et al. (2011) was recurrent
in individuals of Eastern European origin.

Deschauer et al. (2012) identified 3 different mutations in the C19ORF12
gene (614297.0001; 614297.0002; 714296.0007) in 3 patients from 2
unrelated families with NBIA4. All mutations occurred in compound
heterozygosity. The patients had onset in the first or second decades of
upper and lower motor neuron signs reminiscent of juvenile-onset
amyotrophic lateral sclerosis (ALS). Clinical features included pes
cavus, difficulty walking, hypo- and hyperreflexia, muscle weakness and
atrophy, and variable cognitive impairment with neuropsychologic
abnormalities. One patient had optic atrophy. Extrapyramidal signs, such
as parkinsonism, were not present. Brain MRI of all 3 patients showed
T2-weighted hypointensities in the globus pallidus with some
hypointensities also in the substantia nigra and cerebral peduncles,
consistent with iron deposition.

In 2 sisters, born of consanguineous Malian parents, originally reported
by Meilleur et al. (2010) as having autosomal recessive spastic
paraplegia-43 (SPG43; 615043), Landoure et al. (2013) identified a
homozygous missense mutation in the C19ORF12 gene (A63P; 614297.0006).
The mutation was found by exome sequencing of 1 of the sisters.
Sequencing of the coding region of C19ORF12 in 16 Australians, 46
French, 195 Americans, and 170 Japanese presenting with hereditary
spastic paraplegia did not identify any other variants, suggesting that
C19ORF12 mutation is likely a rare cause of this phenotype. Landoure et
al. (2013) identified the same homozygous A63P mutation in 2 sibs from a
consanguineous Brazilian family with NBIA4, and haplotype analysis
indicated a founder effect between the Malian and Brazilian families.
Landoure et al. (2013) suggested that the phenotypic differences between
the 2 families may be due to other genetic or environmental factors or
stochastic effects, and concluded that C19ORF12 mutations cause a
neurologic disease spectrum that may or may not include brain iron
deposition.

*FIELD* AV
.0001
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, 11-BP DEL, NT204

In 13 of 24 Polish probands with neurodegeneration with brain iron
accumulation-4 (NBIA4; 614298), Hartig et al. (2011) identified an 11-bp
deletion (204_214del) in the C19ORF12 gene, resulting in a frameshift
and premature stop codon leading to a predicted truncation of more than
50% of the protein. Immunoblot analysis showed absence of the protein in
patient fibroblasts, consistent with a loss of function. Haplotype
analysis suggested a founder effect, with the mutation occurring at
least 50 to 100 generations earlier. The mutation was not found in 750
control chromosomes. Three additional probands were compound
heterozygous for the 11-bp deletion and another missense mutation in the
C19ORF12 gene (see, e.g., T11M, 614297.0002). The mean age at onset was
9.2 years (range 4 to 20), but most presented before age 11. The most
common presenting symptom was gait or speech difficulty, followed by
extrapyramidal signs, oromandibular and generalized dystonia, and
parkinsonism. Most had progressive involvement of the corticospinal
tract, with spasticity, hyperreflexia, and extensor plantar responses.
Other features included motor axonal neuropathy, optic atrophy, and
cognitive decline. Brain MRI showed hypointensities in the globus
pallidus.

Hogarth et al. (2013) identified the homozygous 11-bp deletion in 3
unrelated patients with NBIA4 of Bosnian, Ukrainian, and mixed Eastern
European ancestry, respectively. Four additional NBIA4 patients,
including a pair of sibs, were compound heterozygous for the 11-bp
deletion and another pathogenic C19ORF12 mutation. All of these patients
were of Polish or other Eastern European ancestry.

.0002
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, THR11MET

In a Polish patient with NBIA4 (614298), Hartig et al. (2011) identified
a homozygous 32C-T transition in the C19ORF12 gene, resulting in a
thr11-to-met (T11M) substitution upstream of the initiation codon of the
shorter isoform, thus only affecting the longer isoform. Another patient
was compound heterozygous for T11M and the founder 11-bp deletion
(614297.0001). The mutation was not found in 750 control chromosomes.

Dogu et al. (2013) identified a homozygous T11M mutation in 3 affected
individuals from 2 unrelated consanguineous Turkish families with NBIA4.
The mutation was found by homozygosity mapping and candidate gene
sequencing. All patients had a relatively late onset of the disorder,
between 25 and 29 years of age, and 2 showed very rapid progression
leading to death 12 and 36 months after admission, respectively. The
features were typical of the disorder, with progressive parkinsonism
unresponsive to L-DOPA therapy, pyramidal signs, and tremor. Two of the
3 patients had cognitive impairment with behavioral abnormalities. Dogu
et al. (2013) suggested that the phenotypic variation in these patients
compared to previously reported NBIA4 patients may be due to the
involvement of other genetic, epigenetic, or environmental factors.

.0003
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, GLY69ARG

In a Polish patient with NBIA4 (614298), Hartig et al. (2011) identified
a homozygous 205G-A transition in the C19ORF12 gene, resulting in a
gly69-to-arg (G69R) substitution in a highly conserved residue in the
transmembrane domain. Another patient was compound heterozygous for G69R
and K142E (614297.0004). The mutation was not found in 750 control
chromosomes.

.0004
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, LYS142GLU

In a Polish patient with NBIA4 (614298), Hartig et al. (2011) identified
compound heterozygosity for 2 mutations in the C19ORF12 gene: a 424A-G
transition resulting in a lys142-to-glu (K142E) substitution and G69R
(614297.0003). The mutation was not found in 750 control chromosomes.
This patient had a relatively mild form of the disorder, with only
impairment of fine motor skills beginning at age 14 years. MRI performed
at age 12 for a pituitary adenoma showed brain iron accumulation as an
incidental finding. This same genotype (G69R and K142E) was found in 1
of 676 patients with parkinsonism. This patient presented with paranoid
hallucinations at age 25 years. By age 49, he was diagnosed with
Parkinson disease, with rigidity, akinesia, and mild tremor. He also had
axial signs, dystonia of the legs with muscle cramps, hypophonia,
hypomimia, vivid dreams, sleep disturbance, optic hallucinations, and
cognitive decline. CT scan showed marked cerebral atrophy, but MRI was
not performed. Both of these patients had a milder form of the disorder
compared to patients with other C19ORF12 mutations.

.0005
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, LEU121GLN

In 2 brothers, born of consanguineous Turkish parents, with NBIA4
(614298), Horvath et al. (2012) identified a homozygous 362T-A
transition in the C19ORF12 gene, resulting in a leu121-to-gln (L121Q)
substitution in a conserved residue. Each unaffected parent was
heterozygous for the mutation, which was not found in 200 control
chromosomes.

.0006
SPASTIC PARAPLEGIA 43, AUTOSOMAL RECESSIVE (1 family)
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4, INCLUDED
C19ORF12, ALA63PRO

In 2 sisters, born of consanguineous Malian parents, originally reported
by Meilleur et al. (2010) as having autosomal recessive spastic
paraplegia-43 (SPG43; 615043), Landoure et al. (2013) identified a
homozygous c.187G-C transversion in the C19ORF12 gene, resulting in an
ala63-to-pro (A63P) substitution at a highly conserved residue in the
membrane domain. The mutation was found by exome sequencing of 1 of the
sisters. The homozygous mutation was not found in 298 Malian controls or
in 951 samples in the ClinSeq cohort. The A63P variant was present in 3
of 3,836 African American alleles in the NHLBI Exome Sequencing Project
database, but not in 8,222 European American alleles in this database.
Sequencing of the coding region of C19ORF12 in 16 Australians, 46
French, 195 Americans, and 170 Japanese presenting with hereditary
spastic paraplegia did not identify any other variants, suggesting that
C19ORF12 mutation is likely a rare cause of this phenotype.
Reexamination of the older sister 5 years after the original report
showed that she had severe atrophy and decreased sensation in the arms
and legs and decreased reflexes, but no cognitive decline, facial or
bulbar weakness, or vision loss. Brain MRI showed no abnormalities and
no iron deposition. Landoure et al. (2013) identified the same
homozygous A63P mutation in 2 sibs from a consanguineous Brazilian
family with onset of walking difficulties due to spastic paraplegia in
their second decade. They had distal muscle wasting and weakness, axonal
sensorimotor neuropathy, and visual loss with optic atrophy. Both became
wheelchair-bound in their thirties. Brain MRI showed evidence of brain
iron deposits in the globus pallidus, consistent with a diagnosis of
NBIA4 (614298). One of the sibs had memory loss and depression.
Haplotype analysis indicated a founder effect between the Malian and
Brazilian families. Landoure et al. (2013) suggested that the phenotypic
differences between the 2 families may be due to other genetic or
environmental factors or stochastic effects, and concluded that C19ORF12
mutations cause a neurologic disease spectrum that may or may not
include brain iron deposition. In vitro functional expression studies in
COS-7 cells showed that the A63P mutant protein had a different
intracellular localization compared to wildtype, with more generalized
distribution throughout the cytoplasm rather than normal localization to
the mitochondria or endoplasmic reticulum.

.0007
NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4
C19ORF12, 3-BP DEL, NT197

In 2 sibs with NBIA4 (614298), Deschauer et al. (2012) identified
compound heterozygous mutations in the C19ORF12 gene: a 3-bp in-frame
deletion (c.197_199del3), resulting in the deletion of a highly
conserved residue Gly33 in the predicted transmembrane domain, and a
T11M substitution (614297.0002). The mother was heterozygous for the
T11M mutation; DNA from the father was not available. The 3-bp deletion
was not found in 1,000 control chromosomes and was absent from 80 HapMap
individuals and the 1000 Genomes Project database. The patients were 27
and 17 years of age at the time of the report. Both had upper and lower
motor neuron signs with pes cavus, winged scapula, and calf atrophy, and
some difficulty walking. One had hyporeflexia with extensor plantar
responses, whereas the other had hyperreflexia with clonus. Nerve
studies showed reduced amplitudes with normal conduction times,
consistent with axonal neuropathy. Both patients also had cognitive
impairment with disinhibited and impulsive behavior; the younger sib had
a history of global developmental delay since age 3 years. A third
unrelated patient with a similar disorder was found to be compound
heterozygous for the 3-bp deletion and an 11-bp deletion (614297.0001).
Each unaffected parent was heterozygous for 1 of the mutations. This
patient had onset of gait difficulties at age 9 years, distal muscle
weakness, hyperreflexia, pes cavus, atrophy of the thenar muscles,
learning difficulties, visual impairment due to optic atrophy, and
emotional lability. Brain MRI of all 3 patients showed T2-weighted
hypointensities in the global pallidus with some hypointensities also in
the substantia nigra and cerebral peduncles, consistent with iron
deposition. Deschauer et al. (2012) noted that the phenotype was
reminiscent of juvenile-onset amyotrophic lateral sclerosis (ALS).

Landoure et al. (2013) identified a homozygous c.197_199del in a patient
with NBIA4. He presented at age 4 years with speech difficulty followed
by progressive spasticity and impaired walking. Other features included
psychomotor slowness, weakness and atrophy of the distal extremities,
and small, pale optic discs. EMG showed denervation consistent with a
motor neuropathy, and brain MRI showed iron deposition in the globus
pallidus. In vitro functional expression studies in COS-7 cells showed
that the mutant protein had a different intracellular localization
compared to wildtype, with more generalized distribution throughout the
cytoplasm rather than normal localization to the mitochondria or
endoplasmic reticulum.

*FIELD* RF
1. Deschauer, M.; Gaul, C.; Behrmann, C.; Prokisch, H.; Zierz, S.;
Haack, T. B.: C19orf12 mutations in neurodegeneration with brain
iron accumulation mimicking juvenile amyotrophic lateral sclerosis. J.
Neurol. 259: 2434-2439, 2012.

2. Dogu, O.; Krebs, C. E.; Kaleagasi, H.; Demirtas, Z.; Oksuz, N.;
Walker, R. H.; Paisan-Ruiz, C.: Rapid disease progression in adult-onset
mitochondrial membrane protein-associated neurodegeneration. Clin.
Genet. 84: 350-355, 2013.

3. Hartig, M. B.; Iuso, A.; Haack, T.; Kmiec, T.; Jurkiewicz, E.;
Heim, K.; Roeber, S.; Tarabin, V.; Dusi, S.; Krajewska-Walasek, M.;
Jozwiak, S.; Hempel, M.; and 13 others: Absence of an orphan mitochondrial
protein, C19orf12, causes a distinct clinical subtype of neurodegeneration
with brain iron accumulation. Am. J. Hum. Genet. 89: 543-550, 2011.

4. Hogarth, P.; Gregory, A.; Kruer, M. C.; Sanford, L.; Wagoner, W.;
Natowicz, M. R.; Egel, R. T.; Subramony, S. H.; Goldman, J. G.; Berry-Kravis,
E.; Foulds, N. C.; Hammans, S. R.; and 9 others: New NBIA subtype:
genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80:
268-275, 2013.

5. Horvath, R.; Holinski-Feder, E.; Neeve, V. C. M.; Pyle, A.; Griffin,
H.; Ashok, D.; Foley, C.; Hudson, G.; Rautensstrauss, B.; Nurnberg,
G.; Nurnberg, P.; Kortler, J.; and 10 others: A new phenotype of
brain iron accumulation with dystonia, optic atrophy, and peripheral
neuropathy. Mov. Disord. 27: 789-793, 2012.

6. Landoure, G.; Zhu, P.-P.; Lourenco, C. M.; Johnson, J. O.; Toro,
C.; Bricceno, K. V.; Rinaldi, C.; Melleur, K. G.; Sangare, M.; Diallo,
O.; Pierson, T. M.; Ishiura, H.; and 19 others: Hereditary spastic
paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum.
Mutat. 34: 1357-1360, 2013.

7. Meilleur, K. G.; Traore, M.; Sangare, M.; Britton, A.; Landoure,
G.; Coulibaly, S.; Niare, B.; Mochel, F.; La Pean, A.; Rafferty, I.;
Watts, C.; Shriner, D.; Littleton-Kearney, M. T.; Blackstone, C.;
Singleton, A.; Fischbeck, K. H.: Hereditary spastic paraplegia and
amyotrophy associated with a novel locus on chromosome 19. Neurogenetics 11:
313-318, 2010.

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2013
Cassandra L. Kniffin - updated: 11/4/2013
Cassandra L. Kniffin - updated: 5/23/2013
Cassandra L. Kniffin - updated: 5/29/2012
Cassandra L. Kniffin - updated: 10/20/2011

*FIELD* CD
Patricia A. Hartz: 10/19/2011

*FIELD* ED
carol: 11/20/2013
ckniffin: 11/12/2013
carol: 11/6/2013
ckniffin: 11/4/2013
alopez: 6/12/2013
ckniffin: 5/23/2013
terry: 7/5/2012
carol: 5/31/2012
ckniffin: 5/29/2012
carol: 10/21/2011
ckniffin: 10/20/2011
mgross: 10/19/2011

MIM 614298
*RECORD*
*FIELD* NO
614298
*FIELD* TI
#614298 NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 4; NBIA4
;;MITOCHONDRIAL PROTEIN-ASSOCIATED NEURODEGENERATION; MPAN
read more*FIELD* TX
A number sign (#) is used with this entry because neurodegeneration with
brain iron accumulation-4 (NBIA4) is caused by homozygous or compound
heterozygous mutation in the C19ORF12 gene (614297) on chromosome 19q12.

DESCRIPTION

Neurodegeneration with brain iron accumulation-4 (NBIA4) is an autosomal
recessive neurodegenerative disorder characterized by progressive
spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and
psychiatric or behavioral symptoms. Other neurologic features, including
optic atrophy, eye movement abnormalities, dystonia, dysphagia,
dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows
T2-weighted hypointensities in the globus pallidus and substantia nigra.
Onset is usually in the first 2 decades, but later onset has been
reported (summary by Dogu et al., 2013). There is phenotypic variation:
some patients may not have extrapyramidal signs and may have muscle
weakness and atrophy as well as cognitive impairment or developmental
delay (Deschauer et al., 2012)

For a general phenotypic description and a discussion of genetic
heterogeneity of NBIA, see NBIA1 (234200).

CLINICAL FEATURES

Hartig et al. (2011) reported 24 Polish patients with neurodegeneration
with brain iron accumulation, including 9 patients from 4 families with
2 or 3 affected sibs. The diagnosis was based on hypointensity in the
globus pallidus documented by T2-weighted cranial MRI. Eighteen of the
patients carried the same deletion mutation (614297.0001) and had a
relatively homogeneous phenotype. The mean age at onset was 9.2 years
(range 4 to 20), but most presented before age 11. The most common
presenting symptom was gait or speech difficulty, followed by
extrapyramidal signs, oromandibular and generalized dystonia, and
parkinsonism. Most had progressive involvement of the corticospinal
tract, with spasticity, hyperreflexia, and extensor plantar responses.
Most retained the ability to walk, but 5 had loss of ambulation
requiring a wheelchair. Eight of 18 (44%) developed a motor axonal
neuropathy, and all had variable optic atrophy. Six of 24 patients had
psychiatric signs, such as impulsive or compulsive behavior, depression,
and emotional lability. None had seizures. Neuropathologic studies from
1 patient showed intracellular iron-containing deposits, axonal
spheroids, numerous Lewy bodies and Lewy body-like inclusions, sparse
Lewy neurites, and hyperphosphorylated MAPT (157140)-containing neuronal
inclusions in various regions. Iron-containing deposits were
concentrated in the globus pallidus and the substantia nigra. There was
loss of myelin in the pyramidal tracts and optic tract.

Horvath et al. (2012) reported 2 brothers, born of consanguineous
Turkish parents, with NBIA4. After early normal development, each
presented at age 7 years with subtly progressive neurologic symptoms,
including intention tremor, dysarthria, cognitive decline, progressive
visual impairment due to optic atrophy, and spasticity with
hyperreflexia and extensor plantar responses. They both remained
ambulatory. Other features included facial hypomimia, orofacial
dystonia, weakness and atrophy of the distal muscles, and axonal
peripheral motor neuropathy. Laboratory studies showed increased serum
creatine kinase; EMG showed neurogenic changes. Brain MRI in the teenage
years showed low-signal intensities in the globus pallidus and
substantia nigra ('eye-of-the-tiger' sign). L-DOPA therapy was
ineffective.

Deschauer et al. (2012) reported 3 patients from 2 unrelated families
with NBIA4. Two sibs were 27 and 17 years of age at the time of the
report. Both had upper and lower motor neuron signs with pes cavus,
winged scapula, and calf atrophy, and some difficulty walking. One had
hyporeflexia with extensor plantar responses and atrophy of the small
muscles of the hand, whereas the other had hyperreflexia with clonus.
Nerve studies showed reduced amplitudes with normal conduction times
consistent with axonal neuropathy. Both patients also had cognitive
impairment with disinhibited and impulsive behavior; the younger sib had
a history of global developmental delay since age 3 years. The third
patient had a similar disorder with onset of gait difficulties at age 9
years, distal muscle weakness, hyperreflexia, pes cavus, atrophy of the
thenar muscles, learning difficulties, visual impairment due to optic
atrophy, and emotional lability. Extrapyramidal signs, such as
parkinsonism, were not present in these patients. Serum creatine kinase
was mildly increased consistent with neurogenic atrophy. Brain MRI of
all 3 patients showed T2-weighted hypointensities in the globus pallidus
with some hypointensities also in the substantia nigra and cerebral
peduncles, consistent with iron deposition. Deschauer et al. (2012)
noted that the phenotype was reminiscent of juvenile-onset amyotrophic
lateral sclerosis (ALS).

Hogarth et al. (2013) reported 23 patients with MPAN confirmed by
genetic analysis. The mean age at onset was 11 years (range 4 to 30
years). Patients most often presented with gait abnormalities and less
commonly with visual impairment due to optic atrophy. Gait abnormalities
were followed by weakness and upper motor neuron signs, including
hyperreflexia affecting the lower limbs more than the upper limbs, and
extensor plantar responses. Later in the disease, lower motor neuron
dysfunction became prominent, with a distal-to-proximal loss of reflexes
and progressive muscle atrophy. Other features included optic atrophy
(in 74% of patients), dysarthria, dysphagia, dystonia, incontinence, and
parkinsonism with a variable response to levodopa treatment. All
patients developed cognitive decline progressing to dementia, and most
had neuropsychiatric changes, such as inattention, hyperactivity,
emotional lability, and depression, as well as stereotypic hand
movements. EMG confirmed the presence of a motor axonopathy in 9
individuals. Two patients who underwent skin or nerve biopsy showed
axonal spheroids. Radiographic findings included increased iron
deposition in the globus pallidus and substantia nigra. Seven patients
had cortical atrophy and 3 had cerebellar atrophy. Neuropathologic
studies of 1 patient affected with dementia and parkinsonism showed
neuronal loss, gliosis, large eosinophilic axonal spheroids, and
widespread deposition of Lewy bodies that stained with alpha-synuclein
(SNCA; 163890). Lewy bodies were present in the cortical, subcortical,
and brainstem regions.

Dogu et al. (2013) reported 3 affected individuals from 2 unrelated
consanguineous Turkish families with NBIA4. All patients had a
relatively late onset of the disorder, between 25 and 29 years of age,
and 2 showed very rapid progression leading to death 12 and 36 months
after admission, respectively. The features were typical of the
disorder, with progressive parkinsonism unresponsive to L-DOPA therapy,
pyramidal signs with hyperreflexia, and tremor. More variable features
included dysarthria, dysphagia, slowed saccadic eye movements, and
dystonia. Brain MRI showed hypointensity in globus pallidus and
substantia nigra. Two of the 3 patients had cognitive impairment with
behavioral abnormalities. Dogu et al. (2013) suggested that the
phenotypic variation in these patients compared to previously reported
NBIA4 patients may be due to the involvement of other genetic,
epigenetic, or environmental factors.

Landoure et al. (2013) reported 2 sibs from a consanguineous Brazilian
family with NBIA4. They had onset of walking difficulties due to spastic
paraplegia in the second decade. Later features included distal muscle
wasting and weakness, axonal sensorimotor neuropathy, and visual loss
with optic atrophy. Both became wheelchair-bound in their thirties. One
of the sibs had memory loss and depression. An unrelated boy with the
disorder was also reported. He presented at age 4 years with speech
difficulty followed by progressive spasticity and impaired walking.
Other features included psychomotor slowness, weakness and atrophy of
the distal extremities, and small, pale optic discs. EMG showed
denervation consistent with a motor neuropathy, and brain MRI showed
iron deposition in the globus pallidus. Genetic analysis in this boy
identified a homozygous mutation in the C19ORF12 gene (614297.0007).

INHERITANCE

Neurodegeneration with brain iron accumulation-4 is an autosomal
recessive disorder (Hartig et al., 2011).

MOLECULAR GENETICS

In 24 Polish patients with NBIA4, Hartig et al. (2011) identified
homozygous or compound heterozygous mutations in the C19ORF12 gene (see,
e.g., 614297.0001-614297.0004). Eighteen patients carried the same 11-bp
deletion (614297.0001), and haplotype analysis indicated a founder
effect. The mutation was initially found after genomewide linkage
analysis of an affected family. Two unrelated patients who were compound
heterozygous for 2 missense mutations (614297.0003 and 614297.0004) had
a milder phenotype. One had only impairment of fine motor skills at age
19 years, and the other presented in his forties with parkinsonism and
dystonia. Hartig et al. (2011) suggested the designation 'mitochondrial
membrane protein associated neurodegeneration (MPAN)' for this disorder.

In 2 brothers, born of consanguineous Turkish parents, with NBIA4,
Horvath et al. (2012) identified a homozygous mutation in the C19ORF12
gene (L121Q; 614297.0005). The mutation was found by homozygosity
mapping followed by exome sequencing.

Deschauer et al. (2012) identified 3 different mutations in the C19ORF12
gene (614297.0001; 614297.0002; 714296.0007) in 3 patients from 2
unrelated families with NBIA4. All mutations occurred in compound
heterozygosity.

In 23 of 161 individuals with NBIA, Hogarth et al. (2013) identified
pathogenic mutations in the C19ORF12 gene. Seventeen patients from 16
families had biallelic mutations, whereas 6 patients from 4 families had
heterozygous mutations; however, the authors considered a second occult
deleterious mutation likely to be present in these patients. The 11-bp
deletion (614297.0001) identified by Hartig et al. (2011) was recurrent
in individuals of Eastern European origin.

In 3 affected individuals from 2 unrelated consanguineous Turkish
families with NBIA4, Dogu et al. (2013) identified a homozygous mutation
in the C19ORF12 gene (T11M; 614297.0002). The mutation was found by
homozygosity mapping and candidate gene sequencing.

In 2 Brazilian sibs with NBIA4, Landoure et al. (2013) identified a
homozygous missense mutation in the C19ORF12 gene (A63P; 614297.0006).
The same homozygous A63P mutation was also found in 2 Malian sisters
with autosomal recessive spastic paraplegia-43 (SPG43; 615043) without
brain iron deposition or cognitive impairment. Haplotype analysis
indicated a founder effect between the Malian and Brazilian families.
Landoure et al. (2013) suggested that the phenotypic differences between
the 2 families may be due to other genetic or environmental factors or
stochastic effects, and concluded that C19ORF12 mutations cause a
spectrum of neurologic disease that may or may not include brain iron
deposition.

*FIELD* RF
1. Deschauer, M.; Gaul, C.; Behrmann, C.; Prokisch, H.; Zierz, S.;
Haack, T. B.: C19orf12 mutations in neurodegeneration with brain
iron accumulation mimicking juvenile amyotrophic lateral sclerosis. J.
Neurol. 259: 2434-2439, 2012.

2. Dogu, O.; Krebs, C. E.; Kaleagasi, H.; Demirtas, Z.; Oksuz, N.;
Walker, R. H.; Paisan-Ruiz, C.: Rapid disease progression in adult-onset
mitochondrial membrane protein-associated neurodegeneration. Clin.
Genet. 84: 350-355, 2013.

3. Hartig, M. B.; Iuso, A.; Haack, T.; Kmiec, T.; Jurkiewicz, E.;
Heim, K.; Roeber, S.; Tarabin, V.; Dusi, S.; Krajewska-Walasek, M.;
Jozwiak, S.; Hempel, M.; and 13 others: Absence of an orphan mitochondrial
protein, C19orf12, causes a distinct clinical subtype of neurodegeneration
with brain iron accumulation. Am. J. Hum. Genet. 89: 543-550, 2011.

4. Hogarth, P.; Gregory, A.; Kruer, M. C.; Sanford, L.; Wagoner, W.;
Natowicz, M. R.; Egel, R. T.; Subramony, S. H.; Goldman, J. G.; Berry-Kravis,
E.; Foulds, N. C.; Hammans, S. R.; and 9 others: New NBIA subtype:
genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 80:
268-275, 2013.

5. Horvath, R.; Holinski-Feder, E.; Neeve, V. C. M.; Pyle, A.; Griffin,
H.; Ashok, D.; Foley, C.; Hudson, G.; Rautensstrauss, B.; Nurnberg,
G.; Nurnberg, P.; Kortler, J.; and 10 others: A new phenotype of
brain iron accumulation with dystonia, optic atrophy, and peripheral
neuropathy. Mov. Disord. 27: 789-793, 2012.

6. Landoure, G.; Zhu, P.-P.; Lourenco, C. M.; Johnson, J. O.; Toro,
C.; Bricceno, K. V.; Rinaldi, C.; Melleur, K. G.; Sangare, M.; Diallo,
O.; Pierson, T. M.; Ishiura, H.; and 19 others: Hereditary spastic
paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum.
Mutat. 34: 1357-1360, 2013.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Face];
Oromandibular dystonia;
[Eyes];
Optic atrophy;
Visual loss, progressive

CHEST:
[Ribs, sternum, clavicles, and scapulae];
Scapular winging

SKELETAL:
[Hands];
Atrophy of the small muscles in the hand;
[Feet];
Pes cavus;
Claw toes

MUSCLE, SOFT TISSUE:
Distal muscle weakness;
Distal muscle atrophy

NEUROLOGIC:
[Central nervous system];
Gait difficulties;
Speech difficulties;
Extrapyramidal signs;
Parkinsonism;
Tremor;
Dystonia;
Oromandibular dystonia;
Ataxia;
Pyramidal signs;
Spasticity;
Hyperreflexia;
Extensor plantar responses;
Upper motor neuron signs, early;
Lower motor neuron signs, later;
Hyporeflexia;
Dysarthria;
Delayed psychomotor development (in some patients);
Cognitive decline;
Dementia;
Iron accumulation in the globus pallidus and substantia nigra seen
on MRI;
Iron-containing deposits in various brain regions;
Lewy bodies;
Axonal spheroids;
Tau-containing inclusions;
Alpha-synuclein-containing inclusions;
Loss of myelin in the pyramidal tracts;
[Peripheral nervous system];
Axonal motor neuropathy (in about 50%);
Reduced nerve amplitudes of peroneal nerve;
[Behavioral/psychiatric manifestations];
Impulsivity;
Compulsions;
Emotional lability;
Depression;
Executive dysfunction

LABORATORY ABNORMALITIES:
Increased serum creatine kinase, mild

MISCELLANEOUS:
Onset usually in first decade;
Later onset has been reported;
Progressive disorder;
Variable phenotype;
Some patients may become wheelchair-bound

MOLECULAR BASIS:
Caused by mutation in the chromosome 19 open reading frame 12 gene
(C19ORF12, 614297.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2013
Cassandra L. Kniffin - updated: 5/23/2013

*FIELD* CD
Cassandra L. Kniffin: 10/20/2011

*FIELD* ED
joanna: 01/14/2014
ckniffin: 11/12/2013
joanna: 7/2/2013
ckniffin: 5/23/2013
ckniffin: 5/29/2012
joanna: 12/29/2011
ckniffin: 10/20/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 11/12/2013
Cassandra L. Kniffin - updated: 11/4/2013
Cassandra L. Kniffin - updated: 5/23/2013
Cassandra L. Kniffin - updated: 5/29/2012

*FIELD* CD
Cassandra L. Kniffin: 10/20/2011

*FIELD* ED
carol: 11/20/2013
ckniffin: 11/12/2013
carol: 11/6/2013
ckniffin: 11/4/2013
alopez: 6/12/2013
ckniffin: 5/23/2013
ckniffin: 4/23/2013
carol: 11/21/2012
terry: 7/5/2012
carol: 5/31/2012
ckniffin: 5/29/2012
carol: 10/21/2011
ckniffin: 10/20/2011

RBCC Red Blood Cell Collection

Full text data of C19orf12