Table 3.

Neurodegeneration with Brain Iron Accumulation: Clinical Characteristics by Genetic Type

NBIA Genetic TypeOnsetTypical PresentationOther Key Clinical Manifestations
PKAN Classic
PKAN		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)
Atypical
PKAN		>10 yrs (w/slower progression)Dysarthria
PLAN
(Parkinson disease 14; PARK14)		Infantile
PLAN
(INAD)		6 mos - 3 yrsDevelopmental regression, initial hypotonia, progressive psychomotor delay, & progressive spastic tetraparesis
  • Progressive cognitive decline
  • Strabismus, nystagmus, & optic atrophy
  • Rapid disease progression
Juvenile
PLAN 1		Typically early childhoodGait instability, ataxia, or speech delay & autistic features
  • Neuropsychiatric disturbances
  • Dystonia & spastic tetraparesis
  • Cognitive decline
  • Slower progression
Adult
PLAN		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

1.

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

2.

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).

3.

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

4.
5.

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

6.

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

7.

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

From: Neurodegeneration with Brain Iron Accumulation Disorders Overview

Cover of GeneReviews®
GeneReviews® [Internet].
Adam MP, Feldman J, Mirzaa GM, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2024.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.