Table 1 NBIA disorders

Classic form: Early onset – rapid progression

Pantothenate kinase-associated neurodegeneration (PKAN)

PANK2

autosomal recessive

Gait abnormality, dystonia, dysarthria, corticospinal involvement, pigmentary retinopathy

“Eye-of-the-tiger” sign in the GP

Mitochondrial membrane protein-associated neurodegeneration (MPAN)

C19orf12

autosomal recessive

Speech and gait difficulties, progressive spastic paraparesis, dystonia, optic atrophy, axonal motor neuropathy, cognitive decline

Increased iron in GP and SN; “Eye of the tiger” sign very rare

Fatty-acid hydroxylase-associated neurodegeneration (FAHN)

FA2H

autosomal recessive

Onset with focal dystonia and gait impairment, ataxia, dysarthria, spastic quadriparesis, nystagmus, visual loss, no or mild cognitive impairment and seizures in late stages; overlaps with some HSP syndromes and phenotypes of leukodystrophies

Abnormal iron in GP and SN, optic, cerebellar and brainstem atrophy, confluent subcortical and periventricular hyperintensity, thinning of the CC

PLA2G6-associated neurodegeneration (PLAN) –Infantile neuroaxonal dystrophy (INAD)

PLA2G

autosomal recessive

Severe psychomotor regression, hypotonia, peripheral motor neuropathy, hyperreflexia, tetraparesis, ataxia, gait abnormalities

Cerebellar atrophy, abnormal iron in GP and other nuclei

Atypical form: Later onset – slower progression

Atypical pantothenate kinase-associated neurodegeneration (PKAN)

PANK2

autosomal recessive

Speech abnormalities, depression, impulsivity, aggression, emotional instability

Eye-of-the-tiger sign or variants of it in the GP or other signs of increased iron and gliosis in the GP

Atypical mitochondrial membrane protein-associated neurodegeneration (MPAN)

C19orf12

autosomal recessive

Psychiatric features, parkinsonism, dystonia-parkinsonism, motor axonal neuropathy, mild gait difficulty, optic atrophy, cognitive decline

Increased iron in GP and SN

Neuroferritinopathy

FTL

autosomal dominant

Huntington´s disease-like presentation: adult-onset chorea or dystonia, orofacial action dystonia, cognitive decline

Abnormal iron and later cystic changes in the basal ganglia

Aceruloplasminemia

CP

autosomal recessive

Diabetes mellitus, retinal degeneration, blepharospasm, facial and neck dystonia, chorea, tremor, dysarthria, ataxia – typically adult onset

Pathological iron in both the brain and viscera; in the brain: GP, striatum, thalami, dentate nuclei

In the viscera: liver

PLA2G6-associated neurodegeneration (PLAN) –neuroaxonal dystrophy (NAD)

PLA2G6

autosomal recessive

Progressive dystonia, dysarthria, language delay, corticospinal signs, psychiatric features and social difficulties or similar to but later onset version of INAD

Cerebellar and optic nerve atrophy

Iron may or may not be increased

PLA2G6-associated neurodegeneration (PLAN) – dystonia-parkinsonism

PLA2G6

autosomal recessive

Parkinsonism, dystonia-parkinsonism

Iron may be increased in SN an striatum

Other NBIA form

Kufor-Rakeb syndrome

ATP13A2

autosomal recessive

Juvenile onset parkinsonism, corticospinal signs, supranuclear gate palsy and cognitive decline, facial-faucial-finger myoclonus, visual hallucinations, oculogyric crisis

Generalized brain atrophy, increased iron in the caudate and lenticular nuclei, but increased iron is not always present

Woodhouse-Sakati Syndrome

C2orf37

autosomal recessive

Hypogonadism, diabetes, alopecia, hearing loss, mental retardation, progressive generalized and focal dystonia, dysarthria, cognitive decline

Increased iron in GP, SN and other nuclei; white matter abnormalities

Static Encephalopathy with Neurodegeneration in Adulthood (SENDA)

In progress

autosomal recessive

Childhood onset cognitive impairment without progression; in adult age sudden onset progressive dystonia-parkinsonism and corticospinal signs.

Increased iron in the GP and SN; on T1W MRI, hyperintensity with central band of hypointensity in the SN; cerebral and cerebellar atrophy