Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). ...This study examined the effect of early ERT on clinical manifestations.
This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively.
Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up.
These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.
Individual inborn errors of metabolism (IEM) are rare disorders, but may not be that uncommon in our patient population. We report the incidence of IEM in a defined cohort of births at the Saudi ...Aramco medical facilities in the Eastern Province of Saudi Arabia over 25 years.
The records of all patients diagnosed with IEM from 1 January 1983 to 31 December 2008 were reviewed and categorized according to accumulated or deficient metabolites into small-molecule disorders (aminoacidemia, organic acidopathies OA, urea cycle defects, fatty acid oxidation, and carbohydrate metabolic disorders) and other disorders, including glycogen and lysosomal storage disorders (LSDs), and organelle disorders.
During the study period, 165,530 Saudi Arabian infants were born at Saudi Aramco and 248 were diagnosed with an IEM, corresponding to a cumulative incidence of 150 cases per 100,000 live births. Small-molecule disorders were diagnosed in 134/248 patients (54%). OA were the most common (48/248 patients; 19%), and methylmalonic aciduria was the most frequently observed OA (13/48 patients; 27%). LSDs were diagnosed in 74/248 patients (30%), and mucopolysaccharidosis was the most frequently observed LSD (28/74; 38%).
We believe that our data underestimate the true incidence of IEM in the region. Regional and national newborn screening programs will provide a better estimation of the incidence of IEM. We recommend a centralized newborn screening program that employs tandem mass spectrometry.
CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 ...unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti- CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient's cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient's p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. Cblb.sup.H257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and Cblb.sup.H257L mice were resistant to suppression by WT Tregs. Bone marrow- derived mast cells from Cblb.sup.H257L mice were hyperactivated after FcepsilonRI cross-linking, and Cblb.sup.H257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.
Mucopolysaccharidosis type IVa (Morquio A syndrome) and mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) are rare inherited lysosomal storage diseases associated with significant functional ...impairment and a wide spectrum of debilitating clinical manifestations. These conditions are thought to have higher-than-average prevalence rates in Saudi Arabia due to high rates of consanguineous marriage in the country. There are several unmet needs associated with the management of these diseases in Saudi Arabia. The consensus statements presented provide specific recommendations to improve diagnostic and treatment approaches, promote multidisciplinary care and data sharing, and optimize the overall management of these rare inherited diseases in Saudi Arabia.
AMPA-type glutamate receptors (AMPARs), key elements in excitatory neurotransmission in the brain, are macromolecular complexes whose properties and cellular functions are determined by the ...co-assembled constituents of their proteome. Here we identify AMPAR complexes that transiently form in the endoplasmic reticulum (ER) and lack the core-subunits typical for AMPARs in the plasma membrane. Central components of these ER AMPARs are the proteome constituents FRRS1l (C9orf4) and CPT1c that specifically and cooperatively bind to the pore-forming GluA1-4 proteins of AMPARs. Bi-allelic mutations in the human FRRS1L gene are shown to cause severe intellectual disability with cognitive impairment, speech delay and epileptic activity. Virus-directed deletion or overexpression of FRRS1l strongly impact synaptic transmission in adult rat brain by decreasing or increasing the number of AMPARs in synapses and extra-synaptic sites. Our results provide insight into the early biogenesis of AMPARs and demonstrate its pronounced impact on synaptic transmission and brain function.
Mucopolysaccharidosis (MPS VI) or Maroteaux-Lamy syndrome is an autosomal recessive lysosomal storage disease caused by deficiency of the enzyme
N
-acetylgalactosamine 4-sulfatase or arylsulfatase B. ...It is involved in the degradation of glycosaminoglycans and characterized by a wide spectrum of clinical and genetic heterogeneity. So far, more than 150 mutations have been reported in the ARSB gene. Most of these mutations are either novel, private, or compound heterozygous making phenotype–genotype correlation as well as population screening difficult. The aim of our study is to determine the genotypes and phenotypes of MPS VI among the Saudi population at the Eastern Province of Saudi Arabia. The clinical data of all the patients seen and diagnosed with MPS VI (Maroteaux-Lamy syndrome) at the main hospital from January 1, 1983, to December 31, 2016, were reviewed. A total of 18 patients from 6 unrelated consanguineous families (first-cousin parents) were diagnosed with MPS VI during the defined 33 years. All of the affected patients displayed the severe phenotype of MPS VI. Only one genotype (c.753C > Gp.Y251X) was identified among five of the studied families. All of those families were inhabitants of Al-Hofuf area, but they descended from different clans. A second genotype (c270_274del5bp pc.91Afs*34) was detected in a single family who had originated from Abha area (the southern-west region of the country). This report demonstrated the homogeneity for both phenotype and genotype of our studied patients with MPS VI. This may eventually make selective asymptomatic carrier test and newborn screening highly feasible in this region of country.
Carnitine-acylcarnitine translocase (CACT) deficiency (McKusick 212138) is a rare life threatening disorder characterized by hypoketotic hypoglycemia, hyperammonemia, encephalopathy, cardiomyopathy ...hepatopathy, and myopathy. Here, we present a detailed clinical course of 3 Saudi siblings with a severe phenotype. The third patient was described in more detail. Early medical intervention in the form of 25% dextrose intravenous infusion and carnitine supplement followed by a gradual introduction of a high carbohydrate low fat special formula resulted in a good clinical and biochemical response to the treatment in our patient. However, early nephrocalcinosis, severe hypotonia, and subsequently intravascular cerebral accident could not be prevented. He died at 18 months of age as a result of metabolic decompensation. This suggests that CACT deficiency is still a lethal disorder even with an early and aggressive medical intervention.
Spinal muscular atrophy (SMA), the most common autosomal recessive cause of infant death, is typically diagnosed by determination of SMN1 copy number. Approximately 3–5% of patients with SMA retain ...at least one copy of the SMN1 gene carrying pathogenic insertions, deletions, or point mutations. We report a patient with SMA who is homozygous for two mutations carried in cis: an 8 bp duplication (c.48_55dupGGATTCCG; p.Val19fs*24) and a point mutation (c.662C>T; p.Pro221Leu). The consanguineous parents carry the same two mutations within one SMN1 gene copy. We demonstrate that a more accurate diagnosis of the disease is obtained through a novel diagnostic assay and development of a capillary electrophoresis method to determine the copy number of their mutant alleles. This illustrates the complexity of SMN mutations and suggests additional testing (gene sequencing) may be appropriate when based on family lines.
We present here the first report of a spinal muscular atrophy (SMA) patient who is homozygous for two allelic mutations carried in cis: an 8 bp duplication (c.48_55dupGGATTCCG; p.Val19fs*24) and a point mutation (c.662C > T; p.Pro221Leu). The consanguineous parents are carriers of the same two mutations within one of their SMN1 gene copies. Our findings illustrate the complexity of SMN mutations and the need for further SMN1/SMN2 quantitation in individuals with SMA.
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