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

Stroke

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

Ataxia

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

[129]

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)

Chorea

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