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Table 1 Less common genetic/neurometabolic causes of dementia, their clinical features, and genetic mutations

From: Early-onset dementias: diagnostic and etiological considerations

Prominent neurological features and disorders Associated clinical features Chromosome/inheritance Protein/gene Screening and diagnostic tests
CADASIL [93] Migraine, psychiatric symptoms 19p13.1-p13.2/autosomal dominant Notch 3 receptor protein (NOTCH3) Skin biopsy - granular deposits in basal lamina of small vessels; NOTCH3 mutation analysis
Stroke, neuropathy     
Fabry disease [117] Skin changes, renal dysfunction, eye findings, heart disease, diarrhea, vomiting and weight loss, stroke and painful peripheral neuropathy Xq22/X-linked α-galactosidase A (GLA) Deficient α-galactosidase A activity in leukocytes and elevated urinary oligosaccharide (trihexoside) assay; GLA mutation analysis
MELAS [117] Short stature, strokes, seizures, migraine, myopathy, peripheral neuropathy, hearing loss, eye findings, cardiomyopathy and conduction abnormalities, diabetes mtDNA/mitochondrial Mitochondrial transfer RNA gene mutations (mtDNA tRNA) EEG; serum and CSF lactate/pyruvate, mtDNA mutation analysis; muscle biopsy showing ragged red fibers
Gaucher disease [124] Hepatosplenomegaly, thrombocytopenia, ataxia, anemia, bleeding, osteopenia, bone abnormalities, growth retardation 1q21/autosomal recessive Glucocerebrosidase (GBA1) Deficient glucocerebrosidase activity in leukocytes; GBA1 mutation analysis
Fragile × tremor-ataxia syndrome [125] Tremor, ataxia, parkinsonism, peripheral neuropathy, dysautonomia Xq27.3/X-linked Fragile × Mental Retardation 1 (FMR1) DNA analysis of CGG trinucleotide repeat expansion demonstrating 55 to 200 repeats (permutation range)
Ataxia, pyramidal     
Adult-onset Tay
Sach's disease/GM2
gangliosidosis [126]
Psychiatric symptoms, cerebellar, upper motor neuron, lower motor neuron, and/or extrapyramidal findings 15q24.1/autosomal recessive Hexosaminidase A (HEXA) Hexosaminidase A levels; HEXA mutation screening
Hereditary diffuse leukoencephalopathy with spheroids [127] Depression, spasticity, ataxia, gait disorder, personality and behavior change, parkinsonism, seizures 5q32/autosomal dominant Colony-stimulating factor 1 receptor (CSF1R) Frontal and parietal white matter hyperintensity on T2/FLAIR MRI; CSF1R mutation analysis
Ataxia, chorea     
Kufs disease/adult-onset neuronal ceroid lipofuscinosis [128] Facial dyskinesia, ataxia, extrapyramidal signs, myoclonic epilepsy, dysarthria 1p32/autosomal recessive Palmitoyl-protein thioesterase 1 (PPT1) in a minority; other genes unknown Tissue biopsy demonstrating ceroid lipofuscin
Dentatorubral-pallidoluysian atrophy
Ataxia, choreoathetosis, psychiatric symptoms 12p13.31/autosomal dominant Atrophin-1 (ATN1) DNA analysis of CAG trinucleotide repeat expansion demonstrating ≥48 repeats
Ataxia, pyramidal, neuropathy     
Cerebrotendinous xanthomatosis [130] Ataxia, peripheral neuropathy, pyramidal signs, psychiatric symptoms, seizures, cataracts, Achilles tendon xanthomas, diarrhea, osteopenia 2q35/autosomal recessive Sterol 26-hydroxylase, mitochondrial (CYP27A1) Elevated serum cholestanol and serum/urine bile alcohols; CYP27A1 mutation analysis
Adrenoleukodystrophy [131] Behavioral change, peripheral neuropathy, myelopathy, Addison's disease Xq28/X-linked ATP-binding cassette transporter, subfamily D, Type 1 (ABCD1) Evidence of dysmyelination on T2/FLAIR MRI (white matter hyperintensity in parieto-occipital, frontal or involving centrum semi-ovale or diffuse); elevated level of very long-chain fatty acids in leukocytes or fibroblasts; ABCD1 mutation analysis
Metachromatic leukodystrophy [132] Pyramidal signs, peripheral neuropathy, behavioral change, psychosis, ataxia, seizures, tremor 22.q13.31-qter and 10q22.1/autosomal recessive Aryl-sulfatase A (ARSA) or saposin B (PSAP) Leukocyte arylsulfatase A assay; urine for elevated sulfatides; ARSA or PSAP mutation analysis
Krabbe disease/globoid cell leukodystrophy [132] Visual problems, gait disorder, rigidity, ataxia, pyramidal signs, peripheral neuropathy 14q31/autosomal recessive Galactocerebroside β-galactosidase (GALC) Leukocyte galactocerebroside β-galactosidase; GALC mutation analysis
Autosomal dominant spinocerebellar ataxias (SCA) [133] Multiple subtypes with most common being: SCA1 - ataxia, pyramidal signs; SCA2 - tremor, ataxia, hyporeflexia, chorea, myoclonus, dystonia, retinal degeneration, cardiac failure; SCA3-peripheral neuropathy, parkinsonism, diplopia, ataxia, dystonia, pyramidal signs, psychiatric symptoms; SCA7 - chorea, parkinsonism, dystonia, ataxia, pyramidal signs, seizures Multiple loci; SCA1 - 6p22.3; SCA2 - 12q24.12; SCA3 - 14q32.12. SCA7 - 3p14.1/autosomal dominant SCA1 - Ataxin-1 (ATXN1); SCA2-Ataxin-2 (ATXN2); SCA3 - Ataxin-3 (ATXN3); SCA7-Ataxin-7 (ATXN7) DNA analysis of CAG trinucleotide repeat expansion in relevant genes
Ataxia, chorea, supranuclear gaze palsy     
Niemann-Pick type C [119] Cerebellar ataxia, dysarthria, dementia, psychiatric disturbances, supranuclear gaze palsy and splenomegaly 18q11 and 14q24.3/autosomal recessive NPC1 and NPC2, respectively Skin fibroblast assay for intracellular cholesterol accumulation (filipin staining); or gene mutation analysis
Ataxia, chorea, parkinsonism     
Wilson's disease [120] Parkinsonism, dystonia, chorea, tremor, psychosis, liver dysfunction, ocular examination for Kayser-Fleischer rings 13q14.3/autosomal recessive ATPase, Cu2+-transporting beta polypeptide, (ATP7B) Screening: serum ceruloplasmin, urinary copper; brain MRI shows 'face of the giant panda' sign Confirmatory: liver biopsy and ATP7B mutation analysis
Parkinsonism, dystonia     
Pantothenate kinase-associated neurodegeneration [134] Dysarthria, psychiatric disturbance, rigidity, dystonia, chorea, gait disturbance 20p13-p12.3/autosomal recessive Pantothenate kinase 2 (PANK2) Mutation analysis of PANK2; MRI pallidal abnormalities with decreased T2 signal intensity, compatible with iron deposits ('eye of the tiger' sign)
Huntington's disease [135] Choreoathetosis, motor impersistence, saccadic eye movements, psychiatric symptoms 4p16.3/autosomal dominant Huntingtin (HTT) c trinucleotide repeat expansion demonstrating ≥36 repeats
  1. Table presents some less common genetic/neurometabolic causes of dementia, their clinical features and genetic mutations grouped according to prominent neurological features. CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CSF, cerebrospinal fluid; EEG, electroencephalogram; FLAIR, fluid-attenuated inversion recovery; MELAS, mitochondrial encephalopathy with lactic acidosis; mtDNA, mitochondrial DNA.