Patrick F. Chinnery

Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency

The human syndrome of dendritic cell, monocyte, B and natural killer lymphoid deficiency presents as a sporadic or autosomal dominant trait causing susceptibility to mycobacterial and other infections, predisposition to myelodysplasia and leukemia, and, in some cases, pulmonary alveolar proteinosis. Seeking a genetic cause, we sequenced the exomes of 4 unrelated persons, 3 with sporadic disease, looking for novel, heterozygous, and probably deleterious variants. A number of genes harbored novel variants in person, but only one gene, GATA2, was mutated in all 4 persons. Each person harbored a different mutation, but all were predicted to be highly deleterious and to cause loss or mutation of the C-terminal zinc finger domain. Because GATA2 is the only common mutated gene in 4 unrelated persons, it is highly probable to be the cause of dendritic cell, monocyte, B, and natural killer lymphoid deficiency. This disorder therefore constitutes a new genetic form of heritable immunodeficiency and leukemic transformation.

Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure

Objective Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement. Methods We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology. Results We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450. Conclusions Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.

Clinical features and natural history of neuroferritinopathy caused by the 458dupA FTL mutation

Sir, In 2007, we described the clinical features and natural history of neuroferritinopathy in 41 patients defined at the molecular genetic level by the presence of Eco N1 restriction digestion site in exon 4 of FTL (also referred to as FTL1 ), the gene coding for the ferritin light polypeptide (Chinnery et al. , 2007). Three French patients in our paper (Cases 13, 36 and 39 in Table 1) had an identical restriction enzyme banding pattern to the original Cumbrian neuroferritinopathy family (Curtis et al. , 2001). Their early clinical course (Caparros-Lefebvre et al. , 1997) and molecular genetic analysis (Chinnery et al. , 2003) had been previously described. We recently received a DNA sample to confirm the diagnosis in a new member of the same French family. Given the recent description of three new FTL mutations (Vidal et al. , 2004; Maciel et al. , 2005; Mancuso et al. , 2005; Ohta et al. , 2008), we now sequence exon 4 of FTL to provide a more comprehensive molecular diagnostic approach. This showed that the new French patient had a different mutation, 458dupA, which segregated with the phenotype in the French family and was not found in 300 European controls. This mutation creates the same Eco N1 restriction site as 460dupA described in the original neuroferritinopathy family (Curtis et al. , 2001), and given that both the French and English pedigrees shared a …

Mitochondrial DNA mutations in neurodegeneration

Mitochondrial dysfunction is observed in both the aging brain, and as a core feature of several neurodegenerative diseases. A central mechanism mediating this dysfunction is acquired molecular damage to mitochondrial DNA (mtDNA). In addition, inherited stable mtDNA variation (mitochondrial haplogroups), and inherited low level variants (heteroplasmy) have also been associated with the development of neurodegenerative disease and premature neural aging respectively. Herein we review the evidence for both inherited and acquired mtDNA mutations contributing to neural aging and neurodegenerative disease. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.

Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation

A 52-year-old Caucasian woman had a non-consanguineous family history of idiopathic autosomal dominant NBIA (a father and a paternal grandmother who both had late onset of abnormal movements at age 60 years). The clinical features of our subject at disease onset (47 years) were dysarthria and orofacial dystonia that were rapidly followed by cerebellar ataxia, asymmetric dysmetria and moderate parkinsonism, with no other symptoms. Hyposignals in T2*-weighted brain magnetic resonance imaging (MRI) suggested iron accumulation in the internal globi pallidi, dentate nuclei, substantia nigra and red nuclei. Serum ferritin and ceruloplasmin levels were normal. A PKAN-2-like phenotype was proposed, as mutations in the PANK-2 gene were negative. Pholipase A2 enzyme encoding gene (PLA2G6), NF ferritin light chain gene (FTL1) genes were excluded. Genetic testing for Friedreich’s ataxia (FA), Huntington’s disease and DYT1 primary torsion dystonia was negative. From June 2002 to November 2007, she progressively and rapidly worsened despite successive trials of symptomatic treatment with levodopa, baclofen, oxitriptan and buspirone. In November 2007, the subject provided informed consent, to allow us to monitor her on deferiprone (30 mg kg 1 day 1 in two doses) for a total of 32 months with weekly blood counts, regular rating using clinical scales and regular MRI scans (Fig. 1). The mean relaxation time (R2*1⁄4 1/T2*) in a T2* sequence acquired with a 1.5 T system (Achieva R2, Philips, the Netherlands) over

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies

Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C. elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.

Current Concepts and Controversies in Neurodegeneration with Brain Iron Accumulation

Neurodegeneration with brain iron accumulation (NBIA) encompasses at least 7 genetically distinct disorders, and additional causative genes likely await identification. Recent advances have included the characterization of new genes associated with new subtypes of NBIA and also highlighted the phenotypic heterogeneity of this class of disorders. Herein, we summarize current concepts of NBIA pathogenesis and discuss important gaps in current knowledge, outlining key questions in the field.

Chapter Five – Neuroferritinopathy

Neuroferritinopathy remains the only autosomal dominant syndrome of neurodegeneration with brain iron accumulation (NBIA). While the majority of identified cases appear to be part of an extended pedigree in the northeast of England, patients are increasingly being identified across the globe. Since its discovery in 2001, there have been significant developments in our understanding of the pathological, radiological, and clinical aspects of the condition, though several key pathomechanistic questions, and crucially treatment paradigms, remain unaddressed. This chapter summarizes the genetic etiology, pathological, radiological, and clinical data from all published data to date and suggested potential new avenues for therapy.

Lower Limb Radiology of Distal Myopathy due to the S60F Myotilin Mutation

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease.

Early neuropsychiatry features in neuroferritinopathy

cations, may be responsible for the tube-related complications. In our case, excessive traction of the tube in a very limited space in the duodenal-jejunal region resulted in the pressure necrosis and ulcers of the duodenal wall near the ampulla, causing increased pressure in the pancreatic duct, which resulted in recurrent pancreatitis. With the likelihood that more PD patients will be receiving duodenal levodopa infusion, the complication of acute pancreatitis should be promptly recognized and managed including the proper evaluation of the position of the tube and the function of the delivery system. Although the problem seems to be primarily gastrointestinal, it is important that neurologists who look after these patients are aware of this potential complication since they will most likely be consulted when these patients experience any problems with the levodopa infusion.