Hagit Flusser

PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum. Progressive white-matter disease and reduction of the N-acetyl aspartate : chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiological diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent). These findings highlight a role of phospholipase in neurodegenerative disorders.

Mutations Disrupting Selenocysteine Formation Cause Progressive Cerebello-Cerebral Atrophy

The essential micronutrient selenium is found in proteins as selenocysteine (Sec), the only genetically encoded amino acid whose biosynthesis occurs on its cognate tRNA in humans. In the final step of selenocysteine formation, the essential enzyme SepSecS catalyzes the conversion of Sep-tRNA to Sec-tRNA. We demonstrate that SepSecS mutations cause autosomal-recessive progressive cerebellocerebral atrophy (PCCA) in Jews of Iraqi and Moroccan ancestry. Both founder mutations, common in these two populations, disrupt the sole route to the biosynthesis of the 21st amino acid, Sec, and thus to the generation of selenoproteins in humans.

Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ

A consanguineous Israeli Bedouin kindred presented with an autosomal-recessive nonlethal phenotype of severe psychomotor retardation and extrapyramidal signs, dystonia, athetosis and ataxia, mild axial hypotonia, and marked global dementia with defects in verbal and expressive communication skills. Metabolic workup was normal except for mildly elevated blood lactate levels. Brain magnetic resonance imaging (MRI) showed increased density in the putamen, with decreased density and size of the caudate and lentiform nuclei. Reduced activity specifically of mitochondrial complex III and variable decrease in complex I activity were evident in muscle biopsies. Homozygosity of affected individuals to UQCRB and to BCSIL, previously associated with isolated complex III deficiency, was ruled out. Genome-wide linkage analysis identified a homozygosity locus of approximately 9 cM on chromosome 5q31 that was further narrowed down to 2.14 cM, harboring 30 genes (logarithm of the odds [LOD] score 8.82 at theta = 0). All 30 genes were sequenced, revealing a single missense (p.Ser45Phe) mutation in UQCRQ (encoding ubiquinol-cytochrome c reductase, complex III subunit VII, 9.5 kDa), one of the ten nuclear genes encoding proteins of mitochondrial complex III.

A Deletion Mutation in TMEM38B Associated with Autosomal Recessive Osteogenesis Imperfecta

Autosomal recessive osteogenesis imperfecta (OI) was diagnosed in three unrelated Israeli Bedouin consanguineous families. Fractures were evident in all cases in infancy. Genome‐wide linkage analysis ruled out association with any of the known OI genes, and identified a single homozygosity locus of approximately 2 Mb on chromosome 9 common to all affected individuals (maximum multipoint lod score 6.5). Whole exome sequencing identified only a single mutation within this locus that was shared by all affected individuals: a homozygous deletion mutation of exon 4 of TMEM38B, leading to an early stop codon and a truncated protein, as well as low TMEM38B mRNA levels. TMEM38B encodes TRIC‐B, a ubiquitous component of TRIC, a monovalent cation‐specific channel involved in Ca2+ release from intracellular stores that has been shown to act in cell differentiation. Molecular mechanisms through which a TMEM38B mutation might lead to an OI phenotype are yet to be explored.

Pelizaeus-Merzbacher-like Disease Caused by AIMP1/p43 Homozygous Mutation

Pelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy caused by PLP1 mutations. A similar autosomal-recessive phenotype, Pelizaeus-Merzbacher-like disease (PMLD), has been shown to be caused by homozygous mutations in GJC2 or HSPD1. We report a consanguineous Israeli Bedouin kindred with clinical and radiological findings compatible with PMLD in which linkage to PLP1, GJC2, and HSPD1 was excluded. Through genome-wide homozygosity mapping and mutation analysis, we demonstrated in all affected individuals a homozygous frameshift mutation that fully abrogates the main active domain of AIMP1, encoding ARS-interacting multifunctional protein 1. The mutation fully segregates with the disease-associated phenotype and was not found in 250 Bedouin controls. Our findings are in line with the previously demonstrated inability of mutant mice lacking the AIMP1/p43 ortholog to maintain axon integrity in the central and peripheral neural system.

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).

COL11A2 mutation associated with autosomal recessive Weissenbacher–Zweymuller syndrome: Molecular and clinical overlap with otospondylomegaepiphyseal dysplasia (OSMED)†

Autosomal recessive Weissenbacher–Zweymuller syndrome (WZS) is a skeletal dysplasia characterized by rhizomelic dwarfism and severe hearing loss. Mutations in the COL11A2 gene have been implicated in causing the autosomal dominant form of this syndrome as well as non‐ocular Stickler syndrome and the autosomal recessive syndrome otospondylomegaepiphyseal dysplasia (OSMED). In a consanguineous Bedouin tribe living in Southern Israel, five individuals affected by autosomal recessive WZS were available for genetic analysis. Homozygosity of a mutation in the COL11A2 gene was found in all affected individuals. This finding lends molecular support to the clinical notion that autosomal recessive WZS and OSMED are a single entity.

UNC80 mutation causes a syndrome of hypotonia, severe intellectual disability, dyskinesia and dysmorphism, similar to that caused by mutations in its interacting cation channel NALCN

Background A syndrome of profound hypotonia, intellectual disability, intrauterine growth retardation with subsequent failure to thrive, dyskinesia and epilepsy was diagnosed in Bedouin Israeli families. Mild dysmorphism was evident: plagiocephaly, broad forehead with prominent nose, smooth philtrum and congenital esotropia. We set out to decipher the molecular basis of this syndrome. Methods Genome-wide linkage analysis and fine mapping were done. Whole exome sequencing data were filtered for candidate variants within locus. Validation and segregation of the mutation was assayed via Sanger sequencing. UNC80 expression pattern was analysed through reverse transcription PCR. Results Homozygosity mapping followed by fine mapping identified a 7.5 Mb disease-associated locus (logarithm of odds score 3.5) on chromosome 2. Whole exome and Sanger sequencing identified a single homozygous nonsense mutation within this locus, segregating within the families as expected for recessive heredity and not found in a homozygous state in 150 Bedouin controls: c.151C>T, p.(R51*) in UNC80. Conclusions The syndrome described is caused by a mutation in UNC80, truncating most of the 3258 amino acids highly conserved encoded protein, that has no known motifs. UNC80 bridges between UNC79 and the cation channel NALCN, enabling NALCNs role in basal Na+ leak conductance in neurons, essential for neuronal function. The phenotype caused by the UNC80 mutation resembles that previously described for homozygous NALCN mutations.

Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation

Foveal hypoplasia, always accompanied by nystagmus, is found as part of the clinical spectrum of various eye disorders such as aniridia, albinism and achromatopsia. However, the molecular basis of isolated autosomal recessive foveal hypoplasia is yet unknown. Individuals of apparently unrelated non consanguineous Israeli families of Jewish Indian (Mumbai) ancestry presented with isolated foveal hypoplasia associated with congenital nystagmus and reduced visual acuity. Genome-wide homozygosity mapping followed by fine mapping defined a 830 Kb disease-associated locus (LOD score 3.5). Whole-exome sequencing identified a single missense mutation in the homozygosity region: c.95T>G, p.(Ile32Ser), in a conserved amino acid within the first predicted transmembrane domain of SLC38A8. The mutation fully segregated with the disease-associated phenotype, demonstrating an ∼10% carrier rate in Mumbai Jews. SLC38A8 encodes a putative sodium-dependent amino-acid/proton antiporter, which we showed to be expressed solely in the eye. Thus, a homozygous SLC38A8 mutation likely underlies isolated foveal hypoplasia.

Pediatricians' communication styles as correlates of global trust among Jewish and Bedouin parents of disabled children.

Objectives: There is a paucity of empirical studies of trust among parents of children with developmental disabilities. Trust is an important element in the patient-physician relationship, especially in medical rehabilitation, where continuous cooperation is essential for positive therapeutic outcomes. Trust is dependent on a variety of psychosocial factors, one of which is the physician’s communication style. The current study had three goals: (1) to compare two groups of Israeli parents, Jews and Bedouins, in terms of the levels of global trust in the pediatricians in a regional child development center; (2) to compare their perceptions of the pediatricians’ communication styles; and (3) to assess the association between three communication styles (caring, interest, and collaboration) and the parents’ trust in the pediatricians. Methods: The sample included 193 parents of disabled children ranging from 6 months to 6 years of age. Global trust and parents’ perceptions concerning their communication with the center’s pediatricians were measured by scales developed for this research. Results: Despite the large cultural differences that exist between the Jewish and Bedouin groups, the only significant difference between them was that Jewish parents’ reported a significantly higher level of collaboration compared with the Bedouins. Global trust in the pediatrician was significantly predicted by the interest and collaboration communication styles, but ethnicity was not a significant predictor. Conclusion: These findings underscore the importance of physicians’ interpersonal competence and skills in the therapeutic relationship and support the increasing trend of including doctor-patient communication training in undergraduate and continuing medical education.