Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.

Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu-Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre- or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders.

Novel mutations and a severe neurological phenotype in Sjögren-Larsson syndrome patients from Iran.

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spasticity and intellectual disability. The disease is caused by mutations in the ALDH3A2 gene that encodes fatty aldehyde dehydrogenase. We describe 7 Iranian SLS patients from 5 unrelated consanguineous families.

Familial Case of Pelizaeus-Merzbacher Disorder Detected by Oligoarray Comparative Genomic Hybridization: Genotype-to-Phenotype Diagnosis.

. Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive hypomyelinating leukodystrophy characterized by nystagmus, spastic quadriplegia, ataxia, and developmental delay. It is caused by mutation in the PLP1 gene.

Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) (MIM #604004) is a rare autosomal recessive neurological disorder characterized by macrocephaly, motor and cognitive decline, ataxia, spasticity and occasional seizures. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen white matter of the cerebral hemispheres and subcortical cysts in the anterior temporal and frontoparietal region. Mutations in MLC1(22q13.

Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.

Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway.

Retinitis pigmentosa, cutis laxa, and pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations.

Gamma-glutamyl carboxylase (GGCX) mutations have been reported in patients with a pseudoxanthoma elasticum (PXE)-like phenotype, loose redundant skin, and multiple vitamin K-dependent coagulation factor deficiencies. We report on the clinical findings and molecular results in 13 affected members of two families who had a uniform phenotype consisting of (PXE)-like skin manifestations in the neck and trunk, loose sagging skin of the trunk and upper limbs, and retinitis pigmentosa confirmed by electroretinographies in 10 affected individuals. There were no coagulation abnormalities.

Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder.

Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (β3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.

Defect in proline synthesis: pyrroline-5-carboxylate reductase 1 deficiency leads to a complex clinical phenotype with collagen and elastin abnormalities.

Pyrroline-5-carboxylate reductase 1 (PYCR1) catalyzes the last step in proline synthesis. Deficiency of PYCR1, caused by a defect in PYCR1, was recently described in patients with cutis laxa, intrauterine growth retardation, developmental dysplasia of the hips and mental retardation. In this paper, we describe additional six patients (ages ranging from 4 months to 55 years) from four Iranian families with clinical manifestations of a wrinkly skin disorder.

Amelia, cleft lip, and holoprosencephaly: a distinct entity.

We report on a male fetus with amelia, cleft lip, and holoprosencephaly. We compare the clinical findings in our patient with those of previously reported cases with the most clinical overlap. To date only four cases with bilateral limb amelia, CNS anomalies, and facial clefts have been described.

Clinical variability in acro-cardio-facial-syndrome.

We report on a 25-year-old man with ectrodactyly and genital anomalies whose parents are first cousins. Their second child died 4 days after birth with severe limb defects and imperforate anus. Our patient may represent clinical variability of the acro-cardio-facial syndrome.

Double de novo mutations of ELA2 in cyclic and severe congenital neutropenia.

Heterozygous mutations of ELA2, encoding the protease neutrophil elastase (NE), cause either autosomal dominant cyclic neutropenia or severe congenital neutropenia (SCN). Three hypotheses have been proposed for how allelic mutations produce these different disorders: 1) disruption of proteolytic activity; 2) mislocalization of the protein; or 3) destabilization of the protein resulting in induction of the unfolded protein response. As with other dominant diseases with reduced reproductive fitness, sporadic cases can result from new mutations not inherited from either parent.