Mutations in MAPKBP1 Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis.

Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis.

GBA2 Mutations Cause a Marinesco-Sjögren-Like Syndrome: Genetic and Biochemical Studies.

Background: With the advent new sequencing technologies, we now have the tools to understand the phenotypic diversity and the common occurrence of phenocopies. We used these techniques to investigate two Norwegian families with an autosomal recessive cerebellar ataxia with cataracts and mental retardation.

Methods And Results: Single nucleotide polymorphism (SNP) chip analysis followed by Exome sequencing identified a 2 bp homozygous deletion in GBA2 in both families, c.

Novel variant: altered respiratory and circadian rhythm, anesthetic sensitivity.

The sodium leak channel, a Na-permeable, nonselective cation channel, is widely expressed in the nervous system, contributing a basal Na-leak conductance and regulating neuronal excitability. A 3-year-old girl, heterozygous for a de novo missense mutation in (c.956C>T; p.

ADCK3 mutations with epilepsy, stroke-like episodes and ataxia: a POLG mimic?

Background And Purpose: Defects of coenzyme Q10 (CoQ10) metabolism cause a variety of disorders ranging from isolated myopathy to multisystem involvement. ADCK3 is one of several genes associated with CoQ10 deficiency that presents with progressive cerebellar ataxia, epilepsy, migraine and psychiatric disorders. Diagnosis is challenging due to the wide clinical spectrum and overlap with other mitochondrial disorders.

Defective PITRM1 mitochondrial peptidase is associated with Aβ amyloidotic neurodegeneration.

Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.

Risk factors and potential preventive measures for nephropatia epidemica in Sweden 2011-2012: a case-control study.

Introduction: Nephropatia epidemica (NE), a relatively mild form of hemorrhagic fever with renal syndrome caused by the Puumala virus (PUUV), is endemic in northern Sweden. We aim to study the risk factors associated with NE in this region.

Methods: We conducted a matched case-control study between June 2011 and July 2012.

High myopia-excavated optic disc anomaly associated with a frameshift mutation in the MYC-binding protein 2 gene (MYCBP2).

Purpose: To investigate the ocular and neurologic manifestations, and to identify the causative mutation in a family with an excavated optic disc anomaly, high myopia, enlarged axial lengths, and abnormal visual evoked response (VER).

Design: Prospective observational case series with whole exome sequencing.

Methods: Institutional study of 8 family members from 3 generations.

STUB1 mutations in autosomal recessive ataxias - evidence for mutation-specific clinical heterogeneity.

Background: A subset of hereditary cerebellar ataxias is inherited as autosomal recessive traits (ARCAs). Classification of recessive ataxias due to phenotypic differences in the cerebellum and cerebellar structures is constantly evolving due to new identified disease genes. Recently, reports have linked mutations in genes involved in ubiquitination (RNF216, OTUD4, STUB1) to ARCA with hypogonadism.

Novel SACS mutations identified by whole exome sequencing in a norwegian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

We employed whole exome sequencing to investigate three Norwegian siblings with an autosomal recessive spastic ataxia and epilepsy. All patients were compound heterozygous (c.13352T>C, p.

Variants of anterior segment dysgenesis and cerebral involvement in a large family with a novel COL4A1 mutation.

Purpose: To investigate the diverse ocular manifestations and identify the causative mutation in a large family with autosomal dominant anterior segment dysgenesis accompanied in some individuals by cerebral vascular disease.

Design: Retrospective observational case series and laboratory investigation.

Methods: Forty-five family members from 4 generations underwent ophthalmic examination.

MRI characterisation of adult onset alpha-methylacyl-coA racemase deficiency diagnosed by exome sequencing.

Background: Correct diagnosis is pivotal to understand and treat neurological disease. Herein, we report the diagnostic work-up utilizing exome sequencing and the characterization of clinical features and brain MRI in two siblings with a complex, adult-onset phenotype; including peripheral neuropathy, epilepsy, relapsing encephalopathy, bilateral thalamic lesions, type 2 diabetes mellitus, cataract, pigmentary retinopathy and tremor.

Methods: We applied clinical and genealogical investigations, homozygosity mapping and exome sequencing to establish the diagnosis and MRI to characterize the cerebral lesions.

Multiple small hyperintense lesions in the subcortical white matter on cranial MR images in two Turkish brothers with cold-induced sweating syndrome caused by a novel missense mutation in the CRLF1 gene.

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder characterized by excess sweating induced by cold exposure, camptodactyly and kyphoscoliosis. CISS is genetically heterogeneous. Deficiency of the CRLF1 or the CLCF1 gene function results in one of two clinically indistuinguishable disorders called CISS1 and CISS2, respectively.

Familial diarrhea syndrome caused by an activating GUCY2C mutation.

Background: Familial diarrhea disorders are, in most cases, severe and caused by recessive mutations. We describe the cause of a novel dominant disease in 32 members of a Norwegian family. The affected members have chronic diarrhea that is of early onset, is relatively mild, and is associated with increased susceptibility to inflammatory bowel disease, small-bowel obstruction, and esophagitis.

Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism.

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries.

A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae.

Purpose: To examine the ocular malformations and identify the molecular genetic basis for autosomal recessive ectopia lentis et pupillae in five Norwegian families.

Methods: Ten affected persons and 11 first-degree relatives of five Norwegian families underwent ophthalmic and general medical examination. Molecular genetic studies included homozygosity mapping with SNP markers, DNA sequencing, and RT-PCR analysis.

Phenotypic variation in a large family with autosomal dominant hypocalcaemia.

Background/aims: Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium- sensing receptor (CASR). We aimed to describe the phenotypic variation within a large family with ADH, especially kidney and cerebral basal ganglia calcifications.

Methods: Fifteen related subjects carrying the CASR mutation T151M participated in a cross-sectional study of calcium homeostasis, renal ultrasonography, cerebral CT, bone mineral density, and health-related quality of life (HRQoL).

Cold-induced sweating syndrome: CISS1 and CISS2: manifestations from infancy to adulthood. Four new cases.

Cold-induced sweating syndrome (CISS), a rare autosomal recessive disorder, is genetically heterogeneous. Deficiency of the CRLF1 and the CLCF1 gene functions results in CISS1 and CISS2, respectively. So far, only a single patient with CISS2 has been reported.

Cold-induced sweating syndrome with neonatal features of Crisponi syndrome: longitudinal observation of a patient homozygous for a CRLF1 mutation.

Cold-induced sweating syndrome (CISS) is a rare autosomal recessive disorder caused by mutations in CRLF1 (cytokine receptor-like factor 1), characterized by profuse sweating in cold environmental temperature and craniofacial and skeletal features. Mutations in CRLF1 also cause Crisponi syndrome (CS), characterized by neonatal-onset paroxysmal muscular contractions as well as craniofacial and skeletal manifestations and abnormal functions of the autonomic nerve system. To date, it is an unresolved problem whether the two conditions are distinct clinical entities or a single clinical entity with variable expressions or with different presentations depending on the patients' age at diagnosis.

Identification of a gene for renal-hepatic-pancreatic dysplasia by microarray-based homozygosity mapping.

We have investigated a family where two siblings had a developmental disorder associated with polycystic dysplastic kidney disease that was incompatible with postnatal survival. Additional features observed were ductal plate malformation in the liver, dysplasia of the pancreas, and (in one individual) complete situs inversus and polymicrogyria of the cingulate gyri. The autopsy findings were compatible with renal-hepatic-pancreatic dysplasia, a condition with unknown genetic cause at the time of autopsy but with similarities to the Meckel-Gruber/Joubert group of recessive ciliopathies.