Neurodegeneration with Brain Iron Accumulation and Infantile Neuroaxonal Dystrophy Panel

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous neurologic disorder characterized by progressive dystonia and dysarthria, parkinsonism, and spasticity. Optic atrophy or retinal degeneration are common symptoms. Neuropsychiatric abnormalities occur in some subtypes. Generalized cerebral atrophy and cerebellar atrophy also frequently present. The age of onset is from infancy to late adulthood with variable progression.

The hallmark feature of NBIA in brain MRI is excess iron accumulation in the basal ganglia, particularly in the globus pallidus and substantia nigra. Pathogenic changes also include Lewy bodies, axonal swellings and hyperphosphorylated tau in certain types of NBIA. The disease is primarily suspected in a patient when brain MRI findings suggest abnormal brain iron accumulation. Different disease types and their associated genes are recognized (Schneider and Bhatia. 2013. PubMed ID: 23212724; Schneider et al. 2013. PubMed ID: 23814539; Arber et al. 2016. PubMed ID: 25870938; Drecourt et al. 2018. PubMed ID: 29395073; Lee et al. 2018. PubMed ID: 29371252).

Infantile neuroaxonal dystrophy (INAD) has early onset from six months to three years with developmental regression, hypotonia, visual disturbance, progressive spastic tetraparesis and motor and mental retardation (Salih et al. 2013. PubMed ID: 24130795; Köroglu et al. 2013. PubMed ID: 23749988; Levi and Finazzi. 2014. PubMed ID: 24847269). Variants in PLA2G6 and NALCN are causative for INAD.

In this NextGen Panel, we sequence genes in which pathogenic variants have been reported in the literature to be causative for NBIA and INAD. This panel covers different types of NBIA disorders and certain other disorders which share phenotype with NBIA. The most important types are listed below:

(1) Pantothenate kinase-associated neurodegeneration (PKAN): also known as Hallervorden-Spatz disease. PKAN is the most common type of NBIA and occurs in approximate two-thirds of NBIA patients.

(2) PLA2G6-associated neurodegeneration (PLAN)

(3) Mitochondrial membrane protein-associated neurodegeneration (MPAN)

(4) Beta-propeller protein-associated neurodegeneration (BPAN)

(5) Fatty acid hydroxylase-associated neurodegeneration (FAHN)

(6) Kufor-Rakeb syndrome, also called Parkinson disease 9.

(7) Neuroferritinopathy

(8) Aceruloplasminemia

(9) COASY protein-associated neurodegeneration

(10) Woodhouse-Sakati syndrome

(11) Infantile neuroaxonal dystrophy (INAD)

This panel for NBIA and INAD contains 16 genes: PANK2, PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, COASY, FTL, CP, DCAF17, GTPBP2, CRAT, REPS1, SCP2, AP4M1 and NALCN. Of these, variants in PLA2G6 and NALCN are causative for INAD, and the remainder causative for NBIA. The vast majority of pathogenic variants in genes in this panel are inherited in an autosomal recessive manner. The exceptions are WDR45 pathogenic variants which are inherited in an X-linked dominant manner and FTL pathogenic variants which are inherited in an autosomal dominant manner. The most important genes in this panel are described briefly below:

PANK2 encodes pantothenate kinase 2 which is an essential regulatory enzyme in CoA biosynthesis, and is located in the mitochondria. Pathogenic variants in PANK2 are causative for pantothenate kinase-associated neurodegeneration (PKAN) which is inherited in an autosomal recessive manner (Leoni et al. 2012. PubMed ID: 22221393; Lee et al. 2016. PubMed ID: 26828213).

PLA2G6 encodes a calcium-independent phospholipases A2 group VI which catalyzes the hydrolysis of the sn-2 acyl-ester bonds in phospholipids. Pathogenic variants in PANK2 are causative for INAD, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism, which are all inherited in an autosomal recessive manner (Salih et al. 2013. PubMed ID: 24130795; Romani et al. 2015. PubMed ID: 25164370).

C19orf12 encodes chromosome 19 open reading frame 12 located on the outer mitochondrial membrane. Pathogenic variants in C19orf12 are causative for mitochondrial membrane protein-associated neurodegeneration (MPAN), which is primarily inherited in an autosomal recessive manner (Hogarth et al. 2013. PubMed ID: 23269600; Tschentscher et al. 2015. PubMed ID: 25592411). However, autosomal dominant inheritance in this disorder has also been documented (Gregory et al. 2019. PubMed ID: 31087512).

WDR45 encodes WD repeat-containing protein. Pathogenic variants in WDR45 are causative for beta-propeller protein-associated neurodegeneration (BPAN), which is inherited in an X-linked dominant manner. The majority of cases are females, however, a few male patients have been reported (Haack et al. 2012. PubMed ID). Most pathogenic variants occur de novo (Haack et al. 2012. PubMed ID: 23176820; Hayflick et al. 2013. PubMed ID: 23687123).

FA2H encodes Fatty acid 2 hydroxylase. Pathogenic variants in FA2H are causative for Fatty acid hydroxylase-associated neurodegeneration (FAHN), which is inherited in an autosomal recessive manner (Arber et al. 2016. PubMed ID: 25870938).

ATP13A2 encodes ATPase type 13A2. Pathogenic variants in ATP13A2 are causative for Kufor-Rakeb syndrome, which is inherited in an autosomal recessive manner (Kruer et al. 2012. PubMed ID: 22743658).

FTL encodes ferritin light chain which aids mineralization within the ferritin structure. Pathogenic variants in FTL are causative for neuroferritinopathy, which is inherited in an autosomal dominant manner (Keogh et al. 2012. PubMed ID: 22278127).

CP encodes ceruloplasmin, which is involved in cellular iron export. Pathogenic variants in CP are causative for aceruloplasminemia, which is inherited in an autosomal recessive manner (Kono and Miyajima. 2006. PubMed ID: 16629161).

COASY encodes coenzyme A synthase, which is in the same metabolic pathway as PANK2 and is a bifunctional enzyme catalyzing the final two steps of CoA synthesis. Pathogenic variants in COASY are causative for COASY protein-associated neurodegeneration (CoPAN), which is inherited in an autosomal recessive manner (Dusi et al. 2014. PubMed ID: 24360804).

DCAF17 encodes DDB1-and-CUL4-associated factor 17. Pathogenic variants in DCAF17 are causative for Woodhouse-Sakati syndrome, which is inherited in an autosomal recessive manner (Alazami et al. 2008. PubMed ID: 19026396).

NALCN encodes nonselective sodium leak channel. Nonsense pathogenic variants in NALCN are causative for INAD, which is inherited in an autosomal recessive manner (Köroglu et al. 2013. PubMed ID: 23749988).

See individual gene test descriptions for more information on molecular biology of gene products and spectra of pathogenic variants.

Pathogenic variants in PANK2 account for 35%-50% of Neurodegeneration with brain iron accumulation, PLA2G6 for 10%, C19orf12 for 6-10%, WDR45 for 1-2%, while pathogenic variants found in other genes in this panel are rare (Gregory and Hayflick 2014. PubMed ID:23447832).

To date, large deletions or duplications have been reported in only a few genes in this panel. Large deletions/duplications have been reported in PLA2G6.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).