Jessica N. Hartley

Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia

Recessive mutations in genes encoding mitochondrial DNA replication machinery lead to mitochondrial DNA depletion syndromes. This genetically and phenotypically heterogeneous group includes infantile onset spinocerebellar ataxia (OMIM# 271245) a neurodegenerative disease caused by mutations in the mtDNA helicase gene, c10orf2, with an increased frequency in the Finnish population due to a founder mutation. We describe a child of English descent who presented with a severe phenotype of IOSCA as a result of two-novel mutations in the c10orf2 gene. This paper expands the phenotypic spectrum of IOSCA and adds further evidence for the presence of a genotype-phenotype correlation among patients with recessive mutations in this gene.

Genetic Counseling in a Busy Pediatric Metabolic Practice

Patients with inborn errors of metabolism and their families require unique clinical care including management of acute illnesses, screening for long term complications, discussion of the etiology of the condition, connections to social supports, and clarification of the recurrence risks and prenatal testing and treatment options. Our multidisciplinary pediatric metabolic clinic combines the skills of metabolic geneticists, pediatric dieticians, social workers, clinical pharmacists, nurses and genetic counselors to provide optimal and well-rounded care for our patients and their families. Given the inherited nature of most inborn errors of metabolism and the necessary long-term management for these disorders, the genetic counselor’s role in this clinic setting is integral in providing ongoing support and education for patients and their families. This includes coping with the disease burden, helping patients and families adapt to a condition in the family and ensuring adequate understanding of the genetic risks and the available prenatal diagnostic and reproductive choices. Our clinic provides services to a large geographic area with many isolated populations where unique metabolic diseases are highly prevalent secondary to a founder effect. In this paper, we share our experience in providing longitudinal care to children with complex medical needs due to metabolic disorders and highlight the role of the genetic counselor in this clinic setting.

Successful therapy for protein-losing enteropathy caused by chronic neuronopathic Gaucher disease

Gaucher disease (OMIM #230800) is caused by β-glucosidase deficiency and primarily involves the mononuclear phagocyte system (also called Reticuloendothelial System or Macrophage System). The disease is classified into three main phenotypes based on the presence or absence of neurological manifestations: non-neuronopathic (type 1), acute neuronopathic (type 2) and chronic neuronopathic (type 3). Typical manifestations include hepatosplenomegaly, skeletal deformities, hematological abnormalities, interstitial lung fibrosis and neurodegeneration in neuronopathic cases. Mesenteric lymphadenopathy with resultant protein losing enteropathy (PLE) has only been rarely described. Mesenteric lymphadenopathy may lead to intestinal lymphatic obstruction and secondary lymphangiectasia resulting in chronic diarrhea, abdominal pain and weight loss. Fecal protein loss with secondary hypoalbuminemia can be significant. We report a male with Chronic Neuronopathic Gaucher disease (GD) (homozygous for c.1448T > C (NM_000157.3) GBA mutation) who at 16 years of age developed intractable abdominal pain, diarrhea and weight loss. This was caused by PLE secondary to intestinal lymphangiectasia caused by calcified mesenteric lymphadenopathy despite prior long term enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT). His older similarly affected sister who had been receiving treatment with ERT and/or SRT remains stable on these treatments with no evidence of mesenteric lymphadenopathy. Medical management with total parenteral nutrition, daily medium chain triglyceride-oil (MCT) supplementation, low dose oral budesonide, continued oral SRT and an increased dose of parenteral ERT has stabilized his condition with resolution of the gastrointestinal symptoms and appropriate weight gain.

Ataxia with oculomotor apraxia type 2 in the Canadian aboriginal population.

To the Editor: Ataxia with oculomotor apraxia type 2 (AOA2) (OMIM 606002) is an autosomal recessive disorder, representing approximately 8% of non-Friedreich autosomal recessive cerebellar ataxias. It is characterized by ataxia onset between 11 and 22 years, and associated with oculomotor apraxia and elevated serum alpha fetoprotein. It was first described in Japanese (1), Pakistani (2) and French Canadian patients (3). We report on affected siblings from a consanguineous family of Ojibwe Canadian Aboriginal descent. The proband presented at age 16 years with insidious and protracted balance difficulties since age 11 years. By 16 years, his symptoms advanced to a noticeably unsteady gait with occasional falls and deterioration in manual dexterity. He was born to healthy parents who are second cousins. His older sister had similar gait abnormality. Reportedly, a paternal first cousin and two maternal first cousins once removed have a similar phenotype. The parents of these individuals are second cousins. These relatives have not presented for a formal evaluation. On examination, his speech was dysarthric and scanning. There was ocular apraxia with initiation of saccades with a head thrust maneuver. He had sustained gaze-evoked nystagmus with lateral gaze. There were no conjunctival telangiectasias. The fine finger and rapid alternating movements were impaired. He displayed symmetric dysmetria on finger-nose-finger and heel-to-shin testing. His gait and stance were broad in base. He was unable to perform tandem walking. The work up included serum alpha fetoprotein (AFP) which was elevated at 20 μg/l (normal 0.0–7.0 μg/l). Brain magnetic resonance imaging revealed cerebellar atrophy affecting the vermis. Chromosome breakage studies did not show evidence of chromosome instability. Mutation analysis of the SETX gene (Prevention Genetics, Marshfield, WI) was performed by polymerase chain reaction amplification of genomic DNA followed by automated sequencing of all the coding exons, as well as 50 bases of flanking non-coding sequences. This revealed a homozygous c.1406A>G (NM_015046.5) mutation predicted to result in the amino acid substitution p.His469Arg. His affected sister was also homozygous for this mutation. Since the early reports of AOA2 in Japanese (1), Pakastani (2) and French Canadian (3) families, it has now been reported in a wide range of populations. This report is the first to document the disease presence in the Canadian Aboriginal population. To date more than 75 mutations have been identified in more than 100 reported patients worldwide. The vast majority of these mutations are distributed across the entire gene without any reported hot spots. Our patients were homozygous for a c.1406A>G, a mutation that has been reported to be causative of AOA2 in a consanguineous family from Southern Italy (4). This substitution was not found in 200 Italian control chromosomes (4) nor did we identify this change in any of the population databases, including dbSNP, 1000Genomes and Exome Aggregation Consortium. In silico analysis using PolyPhen-2, SIFT and MutationTaster predict p.His469Arg change to be ‘probably damaging’, ‘not tolerated’ and ‘disease causing’, respectively (5–7). Based on the recent ACMG guidelines for interpreting sequence variants (8), the c.1406A>G is likely pathogenic. Consanguinity in this family favors the idea of a founder mutation. The presence of the same mutation in the family from Southern Italy is likely a recurrent event and not derived from a single ancestral mutation. This report supports the panethnic presence of AOA2.