Mutations in C2orf37, Encoding a Nucleolar Protein, Cause Hypogonadism, Alopecia, Diabetes Mellitus, Mental Retardation, and Extrapyramidal Syndrome

Alazami, Anas M.; Al-Saif, Amr; Alsemari, Abdulaziz; Bohlega, Saeed; Zlitni, Soumaya; Alzahrani, Fatema; Bavi, Prashant; Kaya, Namik; Çolak, Dilek; Khalak, Hanif; Baltus, Andy; Peterlin, Borut; Danda, Sumita; Bhatia, Kailash P.; Schneider, Susanne A.; Sakati, Nadia; Walsh, Christopher A.; Al‐Mohanna, Futwan; Meyer, Brian F.; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2008.10.018

Cited by 121 publications

(171 citation statements)

References 12 publications

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“…32 Clinically, affected individuals develop progressive dystonia, with or without choreoathetosis. Pyramidal tract involvement is usually not a prominent feature.…”

Section: Wssmentioning

confidence: 99%

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Kruer¹,

Boddaert²,

Schneider³

et al. 2011

AJNR Am J Neuroradiol

190

161

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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.ABBREVIATIONS: ACP ϭ aceruloplasminemia; CNS ϭ central nervous system; FAHN ϭ fatty acid hydroxylase-associated neurodegeneration; INAD ϭ infantile neuroaxonal dystrophy; KRS ϭ KuforRakeb syndrome; NAD ϭ neuroaxonal dystrophy; NBIA ϭ neurodegeneration with brain iron accumulation; NFT ϭ neuroferritinopathy; PKAN ϭ pantothenate kinase-associated neurodegeneration; PLAN ϭ phospholipase-associated neurodegeneration; SENDA ϭ static encephalopathy of childhood with neurodegeneration in adulthood; WSS ϭ Woodhouse-Sakati syndrome B efore the widespread availability of MR imaging, a diagnosis of NBIA could be made only at the time of autopsy. In contrast, current diagnosis is facilitated by evaluation by using both T1-and T2-weighted sequences. As a paramagnetic substance, Fe 3ϩ catalyzes the nuclear spin relaxation of neighboring water protons. With standard clinical parameters, areas rich in iron appear hypointense on T2-weighted sequences, and isointense on T1 sequences. T2*-weighted acquisitions (gradient-echo sequences) may accentuate this degree of hypointensity ("blooming") and may be helpful in identifying NBIA disorders as may susceptibility-weighted images.1 In biologic iron-oxides, Fe 2ϩ typically has fewer unpaired electrons than Fe 3ϩ and is less effective in quenching T2-weighted signal intensity.2 Calcium may also appear isointense on T1 and hypointense on T2-weighted sequences, mimicking the appearance of iron. The 2 minerals are readily distinguished by CT, however, because Ca 2ϩ characteristically appears hyperintense to the surrounding brain parenchyma, while iron is isointense. In addition, iron typically appears markedly hypointense on both standard clinical diffusionweighted and apparent diffusion coefficient sequences. Other metals that may be deposited in neurodegenerative disorders, such as manganese and copper, have a distinct appearance on T1-and T2-weighted sequences, enabling a heuristic approach to diagnosis based on MR imaging parameters. The characteristics of these metals are summarized in Table 1. Despite the utility of MR imaging in this setting, it does not preclude the need for elemental analysis of neuropathologic specimens; rather, it enables putative diagnosis to be made during life.The radiographic appearance of the lesions themselves is of prime importance. Iron deposition occurs in mul...

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“…32 Clinically, affected individuals develop progressive dystonia, with or without choreoathetosis. Pyramidal tract involvement is usually not a prominent feature.…”

Section: Wssmentioning

confidence: 99%

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Kruer¹,

Boddaert²,

Schneider³

et al. 2011

AJNR Am J Neuroradiol

190

161

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“…Increased iron levels in brain have been shown to enhance A toxicity in a Drosophila model [8]. Up to now, seven further genes (PLA2G6, FTL, CP, FA2H, ATP13A2, C2orf37, C19orf12) have been linked to NBIA [9][10][11][12][13][14][15][16][17][18]. Mutations in two of them (PLA2G6, C19orf12) have been identified in patients with idiopathic Parkinson disease underscoring the commonalities between PD and NBIA at the molecular level [19,12].…”

Section: Introductionmentioning

confidence: 99%

Pantothenate Kinase-Associated Neurodegeneration

Hartig

Prokisch²,

Meitinger³

et al. 2012

CDT

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Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis.With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK Drosophila model "fumble" revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012.This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN.

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“…8 Our group has similarly used this phenomenon to identify novel disease-causing genes. 9,10 Increasingly, we have also realized that consanguineous populations lend themselves to "shortcuts" that make the practice of clinical genetics easier in a number of ways, again in the setting of autosomal recessive disorders. Genetically heterogeneous conditions, for example, represent a major challenge in outbred populations where prioritization scheme for mutation analysis usually follows published frequencies of the involved genes.…”

mentioning

confidence: 99%

Homozygosity mapping: One more tool in the clinical geneticist's toolbox

Alkuraya

2010

Genetics in Medicine

Self Cite

115

100

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Consanguinity increases the coefficient of inbreeding, which increases the likelihood of presence of pathogenic mutations in a homoallelic state. Although this is known to have an adverse outcome by increasing the risk of autosomal recessive disorders, this very phenomenon has also made homozygosity mapping the most robust gene discovery strategy in the recent history of human genetics. However, homozygosity mapping can also serve as an extremely powerful tool in the clinical genetics setting as well. In particular, this method is highly suited in the setting of genetically heterogeneous conditions and inborn errors of metabolism that require sophisticated biochemical testing that may not be readily available. This article is meant to highlight the clinical utility of this strategy using illustrative clinical examples from the author's own clinical genetics practice. Genet Med 2010:12(4):236 -239.

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Mutations in C2orf37, Encoding a Nucleolar Protein, Cause Hypogonadism, Alopecia, Diabetes Mellitus, Mental Retardation, and Extrapyramidal Syndrome

Cited by 121 publications

References 12 publications

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Pantothenate Kinase-Associated Neurodegeneration

Homozygosity mapping: One more tool in the clinical geneticist's toolbox

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