C20orf48; HARP; HSS; NBIA1; PKAN
The PANK2 gene is associated with autosomal recessive pantothenate kinase-associated neurodegeneration (PKAN) (MedGen UID: 6708).
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The PANK2 gene encodes the mitochondrial enzyme pantothenate kinase, which plays an essential role in coenzyme A (CoA) biosynthesis and thus in fatty acid metabolism. Disruption of PANK2 and enzyme dysfunction causes progressive neurodegeneration disorders with brain iron accumulation.
PANK2 (NBIA1; OMIM: 606157) is the most common gene associated with the most prevalent form of progressive neurodegeneration with brain iron accumulation (NBIA), pantothenate kinase-associated neurodegeneration I (PKAN), formerly known as Hallervorden-Spatz disease (OMIM: 234200; PMID: 14631201). NBIA is a set of inherited conditions characterized by iron accumulation in the globus pallidus and/or substantia nigra of the basal ganglia (PMID: 28821231). Characteristic signs and symptoms include ataxia, spasticity, progressive dystonia, dysarthria, parkinsonism, neuropsychiatric manifestations, and retinal degeneration (PMCID: 2675558). MRI abnormalities in the globus pallidus and substantia nigra, referred to as the “eye of the tiger” sign, are thought to be pathognomonic for PANK2-associated PKAN (PMID: 12519949, 18443312).
There are two forms of the disorder:
Both groups can exhibit opisthotonus posturing, and this feature is highly suggestive of PKAN (PMID: 28034613).
Acanthocytes have been reported in 10% of PKAN patients (PMID:12510040) and specifically in a cohort of patients from the Dominican Republic who are homozygous for the c.680G>A mutation in the PANK2 gene (PMID: 25915509).
Families with hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) with PANK2 pathogenic variants are thought to fall on the PKAN spectrum (OMIM: 607236; PMID: 12058097).
PKAN can usually be distinguished from the other forms of NBIA by the “eye of the tiger” MRI findings and the absence of seizures that are common with other forms (PMID: 20301663). Over 99% of individuals with the specific MRI findings have pathogenic variants in PANK2 (NBIA International Mutation Database, Oregon Health and Science University, unpublished data).
There are many types of NBIA. Other genes that cause NBIA include: ATP13A2, C19orf12, CP, CoASY, DCAF17, FA2H, FTL, PLA2G6, WDR45, FUCA1, and SQSTM1 (PMID: 20301663).
Disorders with similar features to classic PKAN include (PMID: 20301663, 18981035):
Disorders with similar findings to later-onset, atypical PKAN include (PMID: 20301663, 18981035):
Please note that a patient with a C19orf12 expansion has been reported with the “eye of the tiger” feature (PMID: 21981780).
PANK2 encodes a mitochondrial enzyme that phosphorylates vitamin B5 (known as pantothenate) in one of the first steps in coenzyme A (CoA) biosynthesis (PMID: 25110004). CoA is critical for energy metabolism and fatty acid synthesis and degradation (PMID: 21286947). It is unknown whether iron accumulation is causal or a downstream phenomenon (PMID: 24847269). Along with a deficiency of pantothenate kinase 2, pathogenic variants in PANK2 also result in an accumulation of cysteine-containing cytotoxic substrates (PMID: 11140748). Pathogenic variants in PANK2 account for approximately 50% of NBIA cases in Caucasians (PMID: 18981035).
PANK2-associated NBIA is inherited in an autosomal recessive manner. In the case where only one pathogenic variant in PANK2 is identified and MRI findings are pathognomonic, expert opinion may be useful.
Clinical management interventions and recommendations include (PMID: 28034613):
For dystonia and spasticity, the first-line drugs are trihexyphenidyl for dystonia, and clonazepam and baclofen for spasticity. The second-line drugs include clonidine, gabapentin, tetrabenazine, and pregabalin (PMID: 28034613). Botulinum toxin intramuscular injections can be effective for a period of time in treating rigidity in limbs and facial muscles (PMID: 18981035). Deep-brain stimulation has helped a subset of patients with atypical PKAN (PMID: 21286947). In older patients with parkinsonism, dopaminergic medications are unlikely to be effective (PMID: 28034613).
Treatment-based therapeutics have targeted the biochemical defects using supplementation with pantetheine, pantothenate (vitamin B5), and CoA. Recent consensus guidelines recommend a 3-month course of high-dose pantothenate (PMID: 28034613). Iron chelation studies with deferiprone, which crosses the blood-brain barrier, are ongoing (Clinicaltrials.gov; PMID: 28034613).
Patients with pathogenic PANK2 variants are thought to be deficient in phosphopantothenic acid (PPA), which leads to decreased CoA levels. Ongoing clinical trials are testing a small molecule precursor of PPA called fosmetpantotenate with hopes of bypassing the enzyme deficiency. Unlike 4’-phosphopantothenic acid, fosmetpantotenate can permeate cell membranes (PMID: 28567317).
With ongoing clinical trials, molecular confirmation for PKAN disorders is necessary. If the MRI findings are not pathognomonic for PANK2, NBIA panel testing is recommended.
Review date: October 2017
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