Allison Gregory

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.

Clinical and genetic delineation of neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders characterised by high brain iron and the presence of axonal spheroids, usually limited to the central nervous system. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase associated neurodegeneration (PKAN). More recently, it was found that mutations in the PLA2G6 gene cause both infantile neuroaxonal dystrophy (INAD) and, more rarely, an atypical neuroaxonal dystrophy that overlaps clinically with other forms of NBIA. High brain iron is also present in a portion of these cases. Clinical assessment, neuroimaging, and molecular genetic testing all play a role in guiding the diagnostic evaluation and treatment of NBIA.

T2* and FSE MRI distinguishes four subtypes of neurodegeneration with brain iron accumulation

Background: Neurodegeneration with brain iron accumulation (NBIA) defines a group of genetic disorders characterized by brain iron deposition and associated with neuronal death. The known causes of NBIA include pantothenate kinase-associated neurodegeneration (PKAN), neuroferritinopathy, infantile neuroaxonal dystrophy (INAD), and aceruloplasminemia. Objective: To define the radiologic features of each NBIA subtype. Methods: Brain MRIs from patients with molecularly confirmed PKAN (26 cases), neuroferritinopathy (21 cases), INAD (four cases), and aceruloplasminemia (10 cases) were analyzed blindly to delineate patterns of iron deposition and neurodegeneration. Results: In most cases of PKAN, abnormalities were restricted to globus pallidus and substantia nigra, with 100% having an eye of the tiger sign. In a minority of PKAN cases there was hypointensity of the dentate nuclei (1/5 on T2* sequences, 2/26 on fast spin echo [FSE]). In INAD, globus pallidus and substantia nigra were involved on T2* and FSE scans, with dentate involvement only seen on T2*. By contrast, neuroferritinopathy had consistent involvement of the dentate nuclei, globus pallidus, and putamen, with confluent areas of hyperintensity due to probable cavitation, involving the pallida and putamen in 52%, and a subset having lesions in caudate nuclei and thalami. More uniform involvement of all basal ganglia and the thalami was typical in aceruloplasminemia, but without cavitation. Conclusions: In the majority of cases, different subtypes of neurodegeneration associated with brain iron accumulation can be reliably distinguished with T2* and T2 fast spin echo brain MRI, leading to accurate clinical and subsequent molecular diagnosis.

Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.

Neurodegeneration associated with genetic defects in phospholipase A2

Objective: Mutations in the gene encoding phospholipase A2 group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A2. Methods: We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations. Results: Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations. Conclusion: Defects in phospholipase A2 lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A2 suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.

Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA).

Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult‐onset parkinsonism‐dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA.

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive extrapyramidal disorders with radiographic evidence of focal iron accumulation in the brain, usually in the basal ganglia. Patients previously diagnosed with Hallervorden-Spatz syndrome fall into this category. Mutations in the PANK2 gene account for the majority of NBIA cases and cause an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia and pigmentary retinopathy in children or speech and neuropsychiatric disorders in adults. In addition, a specific pattern on brain MRI, called the eye-of-the-tiger sign, is virtually pathognomonic for the disease. Pantothenate kinase is essential to coenzyme A biosynthesis, and the PANK2 protein is targeted to the mitochondria. Hypotheses of PKAN pathogenesis are based on the predictions of tissue-specific coenzyme A deficiency and the accumulation of cysteine-containing substrates. Identification of the major NBIA gene has led to more accurate clinical delineation of the diseases that comprise this group, a molecular diagnostic test for PKAN, and hypotheses for treatment.Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor-Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder. New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

SUMMARY: NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.

Genetics of Neurodegeneration with Brain Iron Accumulation

The condition originally called Hallervorden-Spatz syndrome is a collection of related disorders involving abnormal iron accumulation in the basal ganglia, usually manifesting with a movement disorder. To date, mutations in the following genes have been associated with neurodegeneration with brain iron accumulation (NBIA) phenotypes: PANK2, PLA2G6, FA2H, ATP13A2, C2orf37, CP, and FTL. This collection, now classified under the umbrella term NBIA, continues to evolve as new genes and associated phenotypes are recognized. As this body of information continues to grow, better approaches to diagnosis and treatment have become available. Continued investigations of the underlying pathogenesis of disease, with a focus on lipid, iron, and energy metabolism, will lead to the identification of new therapeutic targets.

New NBIA subtype Genetic, clinical, pathologic, and radiographic features of MPAN

Objective: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. Methods: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. Results: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase–associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.