Table 3.

Neurodegeneration with Brain Iron Accumulation: Clinical Characteristics by Genetic Type

NBIA Genetic TypeOnsetTypical PresentationOther Key Clinical Manifestations
PKAN Classic
Early (w/rapid progression)Gait abnormalities at age ~3 yrs
  • Progressive dystonia, dysarthria, rigidity, spasticity, hyperreflexia, & extensor toe signs
  • Retinal degeneration is common & may be detected by ERG several yrs before onset of visual symptoms.
  • Neuropsychiatric symptoms (more frequent in later-onset form)
>10 yrs (w/slower progression)Dysarthria
(Parkinson disease 14; PARK14)
6 mos - 3 yrsDevelopmental regression, initial hypotonia, progressive psychomotor delay, & progressive spastic tetraparesis
  • Progressive cognitive decline
  • Strabismus, nystagmus, & optic atrophy
  • Rapid disease progression
Typically early childhoodGait instability, ataxia, or speech delay & autistic features
  • Neuropsychiatric disturbances
  • Dystonia & spastic tetraparesis
  • Cognitive decline
  • Slower progression
Early adulthoodGait disturbance or neuropsychiatric changes
  • Marked cognitive decline
  • Subacute onset of dystonia-parkinsonism
  • Eye movement abnormalities
  • Pyramidal tract signs
MPAN 2Childhood to early adulthoodChildren: gait abnormalities, limb spasticity, optic atrophy
Adults: gait abnormalities, acute neuropsychiatric changes
  • Progressive cognitive decline in most individuals (unlike most NBIA)
  • Neuropsychiatric changes
  • Spasticity (more prominent than dystonia), motor neuronopathy w/early upper-motor neuron findings followed by signs of lower-motor neuron dysfunction
  • Optic atrophy
  • Slowly progressive course w/survival well into adulthood
BPAN ChildhoodDD w/slow motor & cognitive gains & little to no expressive language
  • Seizures of various types more prominent in childhood & may resolve in later adolescence
  • Abnormal behaviors similar to ASD & Rett syndrome
  • Motor dysfunction incl broad-based or ataxic gait, hypotonia, mild spasticity
  • During late adolescence or adulthood, relatively sudden onset of progressive dystonia-parkinsonism & dementia
FAHN ChildhoodMost common presentation is subtle change in gait that may lead to increasingly frequent falls
  • Slowly progressive ataxia, dysarthria, dystonia, & tetraparesis
  • Optic atrophy leading to progressive loss of visual acuity
  • Seizures in later disease course
  • Progressive intellectual decline in most affected individuals
Kufor-Rakeb syndrome 3
(Parkinson disease 9; PARK9)
JuvenileGait abnormalities, neuropsychiatric changes
  • Parkinsonism
  • Dementia
  • Supranuclear gaze palsy
  • Facial-faucial-finger myoclonus
  • Visual hallucinations
  • Oculogyric dystonic spasms 4
Neuroferritinopathy 5AdultMay be similar to Huntington disease w/chorea or dystonia & cognitive changes
  • Progresses from extremity involvement to more generalized movement disorder
  • Characteristic orofacial action-specific dystonia related to speech
Aceruloplasminemia Adult (25-60 yrs)Clinical triad of retinal degeneration, diabetes mellitus, & neurologic disease
  • Facial & neck dystonia, dysarthria, tremors, chorea, ataxia, & blepharospasm
  • ↓ serum concentrations of copper & iron & ↑ serum concentrations of ferritin can distinguish aceruloplasminemia from other forms of NBIA.
Woodhouse-Sakati syndrome (hypogonadism, alopecia, diabetes mellitus, ID, & extrapyramidal syndrome) 6ChildhoodAlopecia may be earliest symptom; ID & delayed puberty
  • Progressive extrapyramidal disorder, generalized & focal dystonia, dysarthria, & cognitive decline
  • Endocrine abnormalities (hypogonadism, alopecia, & diabetes mellitus)
CoPAN 7ChildhoodChildhood-onset dystonia & spasticity w/cognitive impairment
  • Oromandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment, & obsessive-compulsive behavior
  • Slow progression; non-ambulatory in 3rd decade

ASD = autism spectrum disorder; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; DD = developmental delay; ERG = electroretinography; FAHN = fatty acid hydroxylase-associated neurodegeneration; ID = intellectual disability; INAD = infantile neuroaxonal dystrophy; MPAN = mitochondrial membrane protein-associated neurodegeneration; NAD = neuroaxonal dystrophy; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = PLA2G6-associated neurodegeneration


Juvenile PLAN is less common than the infantile form (INAD).


A common C19orf12 founder variant (NM_001031726.3: c.204_214del11; NP_001026896.2: p.Gly69ArgfsTer10) has been observed in persons of central European descent (mainly Polish).


Proposed to be an NBIA based on findings described by Schneider et al [2010] in a family originally reported in 1994


A common FTL pathogenic variant in exon 4 has been found in approximately 80% of affected individuals.


A founder pathogenic variant in DCAF17 accounts for the cases in the Saudi Arabian population.


The CoPAN phenotype will continue to evolve as additional affected individuals are recognized.

From: Neurodegeneration with Brain Iron Accumulation Disorders Overview

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