Genetic studies by NGS Panels 

Panel for Neurodegeneration with Brain Iron Accumulation Disorders (Code 10120)

 

NGS-10120-v15
ATP13A2 C19orf12 COASY CP
DCAF17 FA2H FTL PANK2
PLA2G6 WDR45

 

Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia (most often in the globus pallidus and/or substantia nigra). Generalized cerebral atrophy and cerebellar atrophy are also frequently observed.

The hallmark clinical manifestations of NBIA are progressive dystonia and dysarthria, spasticity, and parkinsonism. Retinal degeneration and optic atrophy are common. Cognitive decline occurs in some subtypes, but more often cognition is relatively spared. Cerebellar atrophy is a frequent finding in some subtypes.

The age of onset ranges from infancy to late adulthood; the rate of progression varies. Progression can be rapid or slow with long periods of stability.

The diagnosis is usually first suspected when brain MRI findings suggest abnormal brain iron accumulation. Clinical findings and molecular genetic testing establish the diagnosis of specific types.

Establishing a diagnosis of a specific NBIA disorder could be done by Brain MRI findings. However, because brain MRI findings in NBIA evolve over time, it may be difficult to determine the diagnosis and establish the specific NBIA disorder, even years after the onset of symptoms. Once abnormal brain iron accumulation is identified, the various types of NBIA can then be considered.

Therefore, ideally the diagnosis of an NBIA disorder should be confirmed with molecular genetic testing: Single gene testing by NBIA type or an NBIA multi-gene panel may be used. A multi-gene panel that includes genes known to be associated with NBIA is likely to be the most cost-effective testing option for many situations.

Types of NBIA and mode of inheritance

Disease Name Gene Inheritance
Pantothenate kinase-associated neurodegeneration (PKAN) PANK2 AR
PLA2G6-associated neurodegeneration (PLAN) PLA2G6 AR
Mitochondrial membrane protein-associated neurodegeneration (MPAN) C19orf12 AR
Beta-propeller protein-associated neurodegeneration (BPAN) WDR45 XLD*
Fatty acid hydroxylase-associated neurodegeneration (FAHN) FA2H AR
Kufor-Rakeb syndrome ATP13A2 AR
Neuroferritinopathy FTL AD
Aceruloplasminemia CP AR
Woodhouse-Sakati syndrome DCAF17 AR
COASY protein-associated neurodegeneration (CoPAN) COASY AR
AR= autosomal recessive; AD= autosomal dominant; *XLD = X-linked dominant (de novo pathogenic variant in WDR45 is inherited in an X-linked dominant manner with suspected male lethality).

If the family-specific pathogenic variant(s) are known, carrier testing for family members at risk for the autosomal recessive types and the X-linked type is possible, and prenatal testing for most types is possible.

The clinical findings of the different genetically defined NBIA types are detailed in the table below.

Disease Name Phenotypes Brain MRI Other
Pantothenate kinase-associated neurodegeneration (PKAN) Classic PKAN (early onset and rapid progression) and atypical PKAN (later onset and slower progression).

Children with PKAN typically manifest gait abnormalities around age three years and later develop progressive dystonia, dysarthria, rigidity, spasticity, hyperreflexia, and extensor toe signs.

Individuals with later-onset PKAN are likely to present with speech difficulty; psychiatric symptoms are more frequent in the later onset form.

Retinal degeneration, a common finding in PKAN, may be detected by electroretinography several years before the onset of visual symptoms.

 

The eye-of-the-tiger sign, T2-weighted hypointense signal in the globus pallidus with a central region of hyperintensity, is virtually pathognomonic for PKAN. HARP syndrome (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is now considered part of the PKAN disease spectrum.

 

PLA2G6-associated neurodegeneration (PLAN) Three phenotypes are observed:

-Infantile neuroaxonal dystrophy (INAD). Manifestations usually begin between ages six months and three years with developmental regression, initial hypotonia, progressive psychomotor delay, and progressive spastic tetraparesis.

-Atypical atypical neuroaxonal dystrophy (NAD). Less common than INAD; manifestations begin later in childhood with slower progression; dystonia and spastic tetraparesis are common. Patients often present with speech delay and diminished social interactions.

-PLA2G6-related dystonia-parkinsonism. Subacute onset of dystonia-parkinsonism occurs in late adolescence/early adulthood. Findings include eye movement abnormalities, pyramidal tract signs, and marked cognitive decline.

In both INAD and atypical NAD, cerebellar atrophy and optic atrophy are hallmark features.

In about half of cases, brain iron accumulation is also observed, usually in the globus pallidus.

Abnormal iron accumulation in the globus pallidus and substantia nigra reported in some individuals with PLA2G6-related dystonia-parkinsonism appears to be variable.

INAD is typically associated with PLA2G6 null variants. PLAN may also be referred to as Parkinson disease 14 or PARK14.
Mitochondrial membrane protein-associated neurodegeneration (MPAN) Defining features of MPAN include 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 course with survival well into adulthood. Unlike most NBIA, the vast majority of individuals with MPAN develop progressive cognitive decline. Other findings are paraparesis or tetraparesis and neuropsychiatric changes. Onset generally occurs in childhood to early adulthood with slow progression and survival well into adulthood.

 

Iron accumulation is observed in both the globus pallidus and substantia nigra; cortical and cerebellar atrophy are common. On T2-weighted images some individuals have hyperintense streaking of the medial medullary lamina between the globus pallidus interna and externa that could be mistaken for an eye-of-the-tiger sign. A common founder variant, C19orf12 (NM_001031726.3: c.204_214del11; NP_001026896.2: p.Gly69ArgfsTer10), has been observed in persons of central European descent (mainly Polish).
Beta-propeller protein-associated neurodegeneration (BPAN) Affected individuals have global developmental delay during childhood with slow motor and cognitive gains; however, during adolescence or adulthood, they experience a relatively sudden onset of progressive dystonia-parkinsonism and dementia.

 

Imaging studies (usually performed because of the onset of movement disorder) typically reveal iron accumulation in the globus pallidus and substantia nigra. T1-weighted signal hyperintensity with a central band of hypointensity in the substantia nigra has also been observed.

 

Reported affected individuals have been simplex cases (i.e., a single occurrence in a family). The majority are females, indicating that pathogenic variants are de novo and suggesting that they are lethal in most males.

 

Fatty acid hydroxylase-associated neurodegeneration (FAHN) FAHN typically begins in childhood and is slowly progressive with focal dystonia in the legs and feet and/or corticospinal tract involvement that often contributes to gait disturbance. Ataxia, dysarthria, and progressive tetraparesis develop later, along with optic atrophy leading to progressive loss of visual acuity. Progressive intellectual decline is reported in most affected individuals.

 

Neuroimaging reveals iron accumulation in the globus pallidus, and to a lesser extent in the substantia nigra. White matter changes and cerebellar and brain stem atrophy increase over time and may be profound.

 

Kufor-Rakeb syndrome Characterized by juvenile-onset parkinsonism, dementia, pyramidal signs, supranuclear gaze palsy, facial-faucial-finger myoclonus, visual hallucinations, and oculogyric dystonic spasms. Similar to PLAN, it has been suggested that only a portion of cases may have iron accumulation, it may develop late in disease course, or it may only be associated with more severe pathogenic variants. Kufor-Rakeb syndrome is also called Parkinson disease 9 or PARK9
Neuroferritinopathy Presentation can be similar to Huntington disease with adult-onset chorea or dystonia and cognitive changes.

Neuroferritinopathy progresses from extremity involvement to a more generalized movement disorder; most affected individuals develop a characteristic orofacial action-specific dystonia related to speech.

Brain MRI shows excess iron in the basal ganglia. The later development of cystic changes and cavitation in the caudate and putamen are unique to neuroferritinopathy. A common FTL pathogenic variant in exon 4 has been found in approximately 80% of affected individuals
Aceruloplasminemia Unlike other forms of NBIA, aceruloplasminemia is characterized by iron accumulation in both the brain and viscera.

The clinical triad of retinal degeneration, diabetes mellitus, and neurologic disease manifests in adulthood (25-60 years).

Neurologic changes include facial and neck dystonia, dysarthria, tremors, chorea, ataxia, and blepharospasm.

 

Brain MRI shows hypointense signal in the globus pallidus, striatum, thalamus, and dentate nucleus on T2-weighted images.

Abnormal hypointensities in the liver are also common; iron content is greater in the liver than in the basal ganglia.

 

Low serum concentrations of copper and iron and high serum concentrations of ferritin can distinguish aceruloplasminemia from other forms of NBIA.
Woodhouse-Sakati syndrome Hypogonadism, Alopecia, Diabetes Mellitus, Intellectual Disability, and Extrapyramidal Syndrome

Neurologic findings include a progressive extrapyramidal disorder, generalized dystonia and focal dystonia, dysarthria, and cognitive decline. Endocrine abnormalities include hypogonadism, alopecia, and diabetes mellitus.

 

 

Decreased signal in the globus pallidus, substantia nigra, and other regions of the basal ganglia on T2-weighted images are consistent with iron accumulation. White matter disease is common. A founder pathogenic variant in DCAF17 accounts for the cases in the Saudi Arabian population
COASY protein-associated neurodegeneration (CoPAN) Presented with early-onset spastic-dystonic paraparesis and later development of oro-mandibular dystonia, dysarthria, axonal neuropathy, parkinsonism, cognitive impairment and obsessive-compulsive behavior.

The affected individuals had slow progression and were alive in their third decades, although they could no longer walk.

Decreased signal in the globus pallidus and substantia nigra on T2-weighted imaging is consistent with iron accumulation.

In one case early in disease, T2-weighted sequences also showed hyperintense and swollen caudate nuclei and putamina and mild hyperintensity in the medial and posterior thalami. The striatal and thalamic changes were not observed later in disease when pallidal hypointensity predominated.

In a different case, central hyperintensity (surrounded by hypointensity) in the globus pallidus was suggestive of an eye-of-the-tiger sign. However, axial CT suggested that the hyperintensities were consistent with calcifications, which is not the case in PKAN.

 

Individuals studied have survived into their third decades despite a severe neurologic phenotype, suggesting the presence of a residual amount of CoA enzymatic activity

 

Treatments for NBIA

Treatments for NBIA are palliative. Treatment of manifestations include (some do not apply to all subtypes of NBIA):  Intrathecal or oral baclofen, oral trihexyphenidyl, intramuscular botulinum toxin, and deep brain stimulation to treat dystonia; services for the blind, educational programs, assistive communication devices; adaptive aids (walkers, wheelchairs) for gait abnormalities.

Interest in iron chelation has re-emerged as data on deferiprone  have accumulated in several patient populations. Iron chelating agents have been tried in the past without clear benefit (Dooling et al 1974). Until recently, trials were limited by the development of systemic iron deficiency before any clinical neurologic benefits were evident. Unlike earlier drugs, deferiprone crosses the blood-brain barrier and removes intracellular iron. Case reports suggest regression of symptoms in two adults with NBIA of unknown cause (i.e., non-PKAN NBIA) (Forni et al 2008, Kwiatkowski et al 2012). A Phase II pilot trial in Italy with ten persons with PKAN found that deferiprone treatment was able to reduce brain iron levels; over the six-month treatment period there were no serious adverse events but also no significant changes in clinical status, suggesting that a longer treatment period is necessary to determine the utility of this drug (Zorzi et al 2011).

Prevention of secondary complications: Adequate nutrition through swallowing evaluation, dietary assessment, gastrostomy tube feeding as needed.

Surveillance: Evaluation for treatable causes of pain during episodes of extreme dystonia; monitoring of height and weight; routine ophthalmologic assessment; regular assessments of ambulation and speech abilities.

 

References

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