Table 2.
NBIA-like forms.
| Gene (OMIM*) |
Disease (OMIM#) Inheritance |
Clinical and MRI Findings | Protein | Function | References |
|---|---|---|---|---|---|
| FBX07 | Parkinson disease 15 (260300) AR |
A girl with a parkinsonian-pyramidal syndrome and brain iron accumulation. Light vermian atrophy progressing to cerebral and cerebellar atrophy, and a hot cross bun sign suggesting ponto-cerebellar tract degeneration. Excessive brain iron deposition in the GP and SN appeared as hypointense signal on iron-sensitive sequences | F-box only protein 7 | Ubiquitin protein ligase involved in ubiquitin proteasome activity and parkin-mediated mitophagy. | [2] |
|
FUCA1 (612280) |
Fucosidosis (230000) AR |
A 14 year-old girl with progressive fixed dystonia and red spots on the skin. Axial T2-weighted images showed slightly hyperintense spot within a hypointense GP and mild hyperintensity of the subcortical white matter consistent with diffuse mild hypomyelination. Over the years, brain atrophy was noticed. | α-L-fucosidase | Lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids. | [3] |
|
GLB1 (611458) |
GM1-gangliosidosis type I (infantile form; 230500) type II (juvenile form; 230600) type III (adult form; 8230650) AR |
Two brothers with the juvenile form of GM1 gangliosidosis. A T2-weighted image revealed significant cerebral atrophy with barely noticeable hypointense signals in GP in the proband (9 years old). The cerebral atrophy and paramagnetic signals in the basal ganglia became more pronounced over the years. His affected brother presented a similar clinical course. | β-galactosidase-1 | Lysosomal hydrolase that cleaves the terminal β-galactose from ganglioside substrates and other glycoconjugates. | [4] |
| A 12 year-old boy with GM1 gangliosidosis type II. MRI revealed a hypointense T2 signal in the SN and in the GP, with marked hypointensity in susceptibility-weighted imaging and slight T2 hyperintensity in the posterior part of the putamen. | [5] | ||||
|
GTPBP2 (607434) |
Jaberi-Elahi syndrome (617988) AR |
Three affected siblings who presented a complex neurologic disorder accompanied with mental deficiency and ataxia and dystonia features. Brain MRI showed cerebellar vermian atrophy, and susceptibility weighted imaging revealed hypointensity signal in the GP and SN suggesting NBIA. | GTP-binding protein 2 | GTP-binding protein that belongs to the GTPase superfamily whose members play a role in a wide variety of biological process (cell proliferation and differentiation, intracellular transport, regulation of cytoskeleton, and protein synthesis). | [6] |
|
SPC2 (184755) |
Leukoencephalopathy with dystonia and motor neuropathy (613724) AR |
Adult-onset disease with brain MRI characteristic of NBIA: T2-weighted imaging showed signal change in the subcortical white matter, thalamus, globus pallidus cerebral peduncles, and pons. Susceptibility-weighted imaging showed signal dropout in the GP, SN, red nuclei, and dentate nuclei | Sterol carrier protein-2 | Peroxisomal enzyme with thiolase activity that is required for the breakdown of branched-chain fatty acids. | [7] |
|
TBCE (604934) |
Encephalopathy with amyotrophy and optic atrophy (617207) AR |
Patients suffering from an early-onset and progressive neurodegenerative encephalopathy with distal spinal muscular atrophy, and brain iron accumulation in the 2nd decade at the level of the GP and SN. | Tubulin folding cofactor E | Chaperone required for the proper tubulin folding and polymerization. | [8] |
|
KMT2B (606834) |
Dystonia 28, childhood-onset (617284) AD |
Several patients suffering from an early-onset progressive dystonia, with subtle, low pallidal signal on T2*, diffusion and susceptibility weighted sequences, particularly affecting the lateral aspect of the GP externa. | Lysine-specific methyltransferase 2B | Histone lysine methyltransferase involved in methylation of histone H3 at lysine 4 (H3K4) | [9] |
|
DDHD1 (614603) |
Spastic paraplegia 28 (609340) AR |
A 55 year-old man with a complex form of spastic paraplegia with retinal dystrophy. MRI revealed a thin corpus callosum, a billateral T2 hyposignal of the internal pallidi and a hypersignal of the supratentorial white matter. | DDHD domain-containing protein 1 | Phospholipase that hydrolyzes phosphatidic acid and attenuates cell activation | [10] |
|
AP4M1 (602296) |
Spastic paraplegia 50 (612936) AR |
Three affected relatives who exhibited very early psychomotor retardation with spasticity and severe mental deficiency. MRI showed global cerebral atrophy, white matter loss asymmetric ventriculomegaly and thining of the splenium of the corpus callosum. T2 sequences revealed symmetric mild hypointensity of the GP. | Adaptor-related protein complex 4 subunit MU-1 | Subunit of the heterotetrameric adaptor protein (AP) complex, which plays a role in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system | [11] |
|
AP4S1 (607243) |
Spastic paraplegia 52 (614067) AR |
AP4 deficiency with ataxia and optic atrophy in a girl who presented with bilateral hypointense signal alterations in the GP in T2-weighted, suggesting abnormal iron accumulation. | Adaptor-related protein complex 4 σ-subunit MU-1 | Subunit of the heterotetrameric adaptor protein (AP) complex, which plays a role in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system. | [12] |
|
RNASEH2B (610326) |
Aicardi-Goutieres syndrome 2 (610181) AR |
Two affected siblings who manifested encephalopathy with spastic quadriplegia and anarthria but preserved intellect. MRI revealed hypointensity of GP on T2, consistent with iron deposition | Ribonuclease H2 subunit B | Subunit of the human ribonuclease H2 enzyme complex that cleaves ribonucleotides from RNA-DNA duplexes. | [13] |
|
LAMAN (609458) |
α-Mannosidosis types I and II (248500) AR |
A 34 year-old man with juvenile onset of α-mannosidosis type II with cerebral and cerebellar atrophy and bilateral hypointensities in the thalamus, GP and putamen on T2-(turbo spin echo; TSE)-weighted images, suggestive of iron accumulation. The SN and red nucleus were also hypointense on T2-(TSE)-weighted images. The basal ganglia were isointense on T1-weighted images. | α-mannosidase | Lysosomal hydrolase that cleaves α-linked mannose residues from the nonreducting end of N-linked glycoproteins. | [14] |
|
REPS1 (614825) |
NBIA 7 (617916) AR |
Two sisters affected by an early-onset condition (trunk hypotonia, progressive cerebellar ataxia, pyramidal syndrome). MRI of the proband at age of 15 showed progressive cerebellar and cerebral atrophy, and hypointensity of the SN and GP consistent with iron deposition. Her affected sister at age of 2 showed no alterations. | RALBP1-associated Eps domain-containing protein 1 | Protein involved in endocytosis and vesicular transport. REPS1 interacts with endocytic scaffold intersectin 1, an essential player in clathrin-mediated endocytosis. | [15] |
|
CRAT (600184) |
NBIA 8 (617917) AR |
A girl suffering from an early-onset condition with slowly progressive spinocerebellar degeneration. MRI showed cerebellar atrophy and posterior leukodystrophy at 15.5 years old, besides of hypointensity of the SN and GP consistent with iron deposition. | Carnitine acetyltransferase | Enzyme involved in the control of the acyl-CoA/CoA ratio in mitochondria, peroxisomes, and endoplasmic reticulum. | [15] |
|
MANEAL (NA) OSTM1 (607649) |
NA Osteopetrosis (259720) AR |
Boy, carrier of homozygous mutations in MANEAL and OSTM1, with an early-onset complex neurodegenerative disorder. MRI demonstrated massive brain atrophy and symmetrical iron accumulation in GP, corpora mamillaria and cerebral peduncles, which may due to defects on MANEAL. | Mannosidase endo-α like protein Ostepetrosis-associated transmembrane protein 1 |
Unknown function/OSTM1 plays a role in subcellular endosome/lysosome dispersion and autophagy processes, which may be related to lysosomal dysfunction. | [16] |
|
MTSS1L (616957) |
NA AR |
A 10 year-old girl with microcephaly, intellectual disability, developmental delay, and hypotonia. Brain MRI at 5 years of age was unremarkable, and when repeated at age of 10, showed iron accumulation in GP bilaterally. Her sister (7 years) is similarly affected; her MRI at age of 14 months did not show iron deposition. | Metastasis suppressor 1-like | Protein involved in plasma membrane dynamics that has a conserved N-terminal domain (IRSP53/MIM homology domain or an inverse BAR domain). | [17] |
|
VAC14 (604632) |
Striatonigral degeneration childhood-onset (617054) AR |
Two siblings affected by retinitis pigmentosa and an early childhood severe progressive spastic paraparesis with learning disabilities. MRI revealed at age of 9, decreased signal of the GP and SN (axial T2*) and striatal T2 prolongation (axial T2). | VAC14 or ArPIKfyve (associated regulator of the PIKfyve complex) | Component of the PIKfyve complex that tightly regulates the level of PtdIns(3,5)P2 in endosomal membranes. | [18] |
OMIM: online mendelian inheritance in man, https://www.omim.org/; MIM*: gene; MIM#: phenotype; NBIA: neurodegeneration with brain iron accumulation; MIM: mendelian inheritance in man; AR: autosomal recessive; AD: autosomal dominant; MRI: magnetic resonance imaging; GP: globus pallidus; SN: substantia nigra.