Table 2.

Disorders to Consider in the Differential Diagnosis of FAHN

PhenotypeDiffDx DisorderGene(s)MOIAdditional Clinical & MRI Features of DiffDx Disorder
Overlapping w/FAHNDistinguishing from FAHN
Other NBIA disorders MPAN C19orf12 AR
  • Cognitive decline
  • Progressive spasticity & dystonia
  • Optic atrophy
  • Hyperintense streaking of medial medullary lamina often observed on T2-weighted MRI
  • Parkinsonism developing in later disease
PKAN PANK2 ARProgressive dystonia & dysarthria
  • "Eye of the tiger" sign
  • More severe dystonia
Juvenile PLAN (atypical NAD) PLA2G6 AR
  • Progressive spasticity & dystonia
  • Optic atrophy
  • Cognitive decline
  • Cerebellar atrophy
  • Fewer cerebellar findings
  • Apparent claval hypertrophy
CoPAN COASY ARChildhood-onset gait abnormalities w/cognitive/psychiatric features
  • More prominent extrapyramidal signs
  • Pallidal iron
Neurodegenerative mineral deposition disorder Wilson disease ATP7B AR
  • Gait disturbance
  • Spasticity
  • Dystonia
  • T2-weighted hypointensity of globus pallidus
  • Kayser-Fleischer rings
  • Liver disease (most common 1st manifestation of Wilson disease in children)
Clinical mimics w/spasticity, dystonia, ataxia, or combination
Hereditary ataxia Friedreich ataxia FXN AR
  • Spastic paraplegia
  • Dysarthria
  • Optic atrophy
  • Peripheral neuropathy
  • Cerebellar atrophy
  • More prominent early gait ataxia (cerebellar & proprioceptive)
  • Absence of early spasticity
  • Cardiomyopathy
  • Diabetes mellitus in later stages
  • Prominent cervical cord atrophy & only later-onset cerebellar atrophy on MRI
  • Early childhood spastic ataxia
  • Oculomotor abnormalities
  • Teenage-onset of seizures
  • Unsteady at onset of gait
  • Hypermyelinated retinal fibers
  • Polyneuropathy
PLP1 null syndrome (See PLP1-Related Disorders.) PLP1 XLChildhood-onset spasticity & ataxiaMultifocal demyelinating polyneuropathy
Spastic paraplegia 2 (See PLP1-Related Disorders.) PLP1 XL
  • Childhood-onset spasticity ± ataxia
  • Nystagmus
  • Preserved cognition
  • Milder course
Spastic paraplegia 44 GJC2 AR
  • Spasticity
  • Hyperreflexia
  • Intention tremor
  • Preservation of basal ganglia & no cerebellar atrophy
  • Diffuse hypomyelination on MRI
Spastic paraplegia 11 SPG11 AR
  • Spastic paraparesis
  • Mild cognitive delay
  • Cerebellar & bulbar involvement
  • Periventricular white matter abnormalities & thin corpus callosum on MRI
More frequent peripheral neuropathy
Spastic paraplegia 15 ZFYVE26 AR
Arylsulfatase A deficiency (juvenile metachromatic leukodystrophy) ARSA AR
  • Early childhood motor regression
  • Spasticity
  • Dysarthria
  • Behavior & cognitive ability decline first
  • More frequent peripheral neuropathy
  • Periventricular demyelination on MRI
Hypomyelination with atrophy of the basal ganglia and cerebellum (See TUBB4A-Related Leukodystrophy.) TUBB4A AR
  • Variable-onset motor regression w/spasticity
  • Dystonia
  • Bulbar & cerebellar dysfunction
  • Cerebellar atrophy on MRI
  • More prominent extrapyramidal features
  • Diffuse hypomyelination, atrophy of caudate & putamen, preservation of globus pallidus on MRI
POLR3-related leukodystrophy POLR3A
  • Spasticity
  • Tremor
  • Extrapyramidal symptoms
  • MRI: thin corpus callosum w/cerebellar atrophy.
  • Cerebellar features predominate
  • Abnormal dentition
  • Endocrine abnormalities
  • ± myopia
  • Hypomyelination pattern on MRI
Other disordersJuvenile & chronic hexosaminidase A deficiency HEXA AR
  • Childhood or later onset spasticity, ataxia, & seizures
  • ± optic atrophy
  • ± cerebellar atrophy
  • ± retinitis pigmentosa
  • Juvenile form more aggressive
GTP cyclohydrolase 1-deficient dopa-responsive dystonia GCH1 ARChildhood-onset gait abnormalities, spasticity, & brisk reflexes
  • Diurinal fluctuation
  • Improvement w/low-dose levodopa
  • MRI: normal

AD = autosomal dominant; AR = autosomal recessive; ARSACS = autosomal recessive spastic ataxia of Charlevoix Saguenay; DiffDx = differential diagnosis; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; XL = X-linked

From: Fatty Acid Hydroxylase-Associated Neurodegeneration

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