Our team has authored a comprehensive NBIA Disorders Overview, posted as a GeneReview (linked below), that describes the NBIA disorders, associated genes, differential diagnoses and establishing a diagnosis of NBIA, and general management guidelines.
Idiopathic NBIA
Approximately 30% of cases of NBIA remain idiopathic, despite the growing number of causative genes that have been identified. With more common use of whole exome sequencing (WES) in the clinical arena, additional unrecognized cases of NBIA are being identified.
This new ascertainment through WES continues to contribute to “phenotype expansion” in the various forms of NBIA.
PKAN
PKAN (Pantothenate Kinase-Associated Neurodegeneration) is an NBIA disorder with a phenotypic spectrum that includes classic PKAN (early onset and rapid progression) and atypical PKAN (later onset and slower progression). Children with PKAN have characteristic symptoms that include gait abnormalities, progressive dystonia, dysarthria, and spasticity, and retinal degeneration. Individuals with later-onset PKAN are likely to present with speech difficulty and frequently have neuropsychiatric symptoms.
Our team has authored a comprehensive GeneReview (linked below) that explains the full natural history of PKAN, its genetic cause, diagnostic criteria, treatment/management options and surveillance recommendations.
PLAN
PLAN (PLA2G6-Associated Neurodegeneration) is an NBIA disorder characterized by three distinct phenotypes:
- INAD (infantile neuroaxonal dystrophy) has symptoms that include developmental regression, progressive psychomotor delay, optic atrophy, and initial truncal hypotonia followed by later spastic tetraparesis
- aNAD (atypical neuroaxonal dystrophy) has symptoms that include speech delay, diminished social interactions, spastic tetraparesis and dystonia, which begin later in childhood and progress more slowly than in INAD.
- PLA2G6-related Dystonia-Parkinsonism has symptoms that include subacute onset of dystonia-parkinsonism in late adolescence to early adulthood, eye movement abnormalities, pyramidal tract signs, and marked cognitive decline and neuropsychiatric symptoms.
Our team and our collaborators have co-authored a comprehensive GeneReview (linked below) that explains the full natural history of PLAN, its genetic cause, diagnosis criteria, treatment/management options and surveillance recommendations.
MPAN
MPAN (Mitochondrial Membrane Protein-Associated Neurodegeneration) is an NBIA disorder characterized by spasticity that is more prominent than dystonia, optic atrophy, a motor neuronopathy with early upper-motor neuron findings followed later by signs of lower-motor neuron dysfunction, and a slowly progressive disease course. The majority of individuals with MPAN develop progressive cognitive decline.
Our team and our collaborators have co-authored a comprehensive GeneReview (linked below) that explains the full natural history of MPAN, its genetic cause, diagnosis criteria, treatment/management options and surveillance recommendations.
BPAN
BPAN (Beta-Propeller Protein-Associated Neurodegeneration) is an NBIA disorder characterized by childhood-onset global developmental delay with slow motor and cognitive gains. During adolescence or adulthood, patients develop progressive dystonia-parkinsonism and additional cognitive decline.
Pubmed articles about BPAN:
– BPAN: the only X-linked dominant NBIA disorder
– Beta-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation
– Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients
FAHN
FAHN (Fatty Acid Hydroxylase-Associated Neurodegeneration) is an NBIA disorder characterized by focal dystonia in the legs and feet and/or corticospinal tract involvement that often contributes to gait disturbance. Other hallmark features include ataxia, dysarthria, progressive spastic paraparesis or tetraparesis, and optic atrophy develop. Progressive intellectual decline has been reported in most affected individuals.
Our team and our collaborators have co-authored a comprehensive GeneReview (linked below) that explains the full natural history of FAHN, its genetic cause, diagnosis criteria, treatment/management options and surveillance recommendations.
Kufor-Rakeb syndrome
Kufor-Rakeb syndrome is an NBIA disorder characterized by juvenile-onset parkinsonism, dementia, pyramidal signs, facial-faucial-finger myoclonus, supranuclear gaze palsy, oculogyric dystonic spasms and visual hallucinations.
Pubmed articles about Kufor-Rakeb syndrome:
– Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations
– ATP13A2 mutations (PARK9) cause neurodegeneration with brain iron accumulation
– Novel mutation in ATP13A2 widens the spectrum of Kufor-Rakeb syndrome (PARK9)
Neuroferritinopathy
Neuroferritinopathy is an NBIA disorder characterized by symptoms that can be similar to Huntington’s disease with adult-onset chorea or dystonia and cognitive changes. Neuroferritinopathy progresses from extremity involvement to a more generalized movement disorder, and most affected individuals develop a characteristic orofacial action-specific dystonia related to speech.
Dr. Patrick Chinnery has authored a comprehensive GeneReview (linked below) that explains the full natural history of neuroferritinopathy, its genetic cause, diagnosis criteria, treatment/management options and surveillance recommendations.
Aceruloplasminemia
Aceruloplasminemia is an NBIA disorder characterized by iron accumulation in both the brain and viscera, which is not seen in any other NBIA disorder. The symptoms of aceruloplasminemia include retinal degeneration, diabetes mellitus, and adult-onset neurologic disease. Some neurologic changes that have been observed are facial and neck dystonia, dysarthria, tremors, chorea, ataxia, and blepharospasm.
Dr. Hiraoki Miyajima has authored a comprehensive GeneReview (linked below) that explains the full natural history of aceruloplasminemia, its genetic cause, diagnosis criteria, treatment/management options and surveillance recommendations.
Woodhouse-Sakati syndrome
Woodhouse-Sakati syndrome is an NBIA disorder characterized by both neurologic and endocrine symptoms, which is not seen in any other NBIA disorder. Neurologic findings include a progressive extrapyramidal disorder, generalized and/or focal dystonia, dysarthria, and cognitive decline. Endocrine abnormalities include hypogonadism, alopecia, and diabetes mellitus.
Pubmed articles about Woodhouse-Sakati syndrome:
-A syndrome of hypogonadism, alopecia, diabetes mellitus, mental retardation, deafness, and ECG abnormalities
– Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1
CoPAN
CoPAN (COASY Protein-Associated Neurodegeneration) is a newly-discovered NBIA disorder with a phenotype that continues to evolve as further cases are identified. Based on the few subjects that have been described to date, symptoms of CoPAN can include early-onset spastic-dystonic paraparesis and later development of oromandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment and obsessive-compulsive behavior.
– Exome sequence reveals mutations in CoA synthase as a cause of neurodegeneration with brain iron accumulation