In the folate cycle MTHFD1, encoded by
MTHFD1
, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and ...10-formyltetrahydrofolate synthetase activity. To date, only one patient with
MTHFD1
deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590–2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from
14
C-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.
Background
Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50 % the etiology remains unknown. Recently biallelic mutations in
NBAS
were identified as a ...new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF).
Methods
The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients’ fibroblasts.
Results
The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients’ fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi.
Conclusions
Mutations in
NBAS
cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.
To describe the health status of young patients affected by inborn errors of metabolism that require adherence to a restricted diet (IEMRDs) and to describe and compare their self- and proxy ...(parent)-reported quality of life (QoL) with reference values.
A cross-sectional study was conducted in 2015-2017 in patients affected by IEMRDs (except phenylketonuria) younger than 18 years. Data collection was based on medical records, clinical examinations, parents' and children's interviews, and self-reported questionnaires. Measurements included clinical and healthcare data, child and family environment data, and self- and proxy (parent)-reported QoL.
Of the 633 eligible participants, 578 were recruited (50.3% boys; mean age: 8.7 years); their anthropometric status did not differ from the general population. Approximately one-half of them had at least 1 complication of the disease. Their self-reported global QoL did not differ from that of the general population. However, relations with friends and leisure activities QoL domains were negatively impacted, whereas relations with medical staff, relations with parents, and self-esteem QoL domains were positively impacted. Their proxy (parent)-reported QoL was negatively impacted.
Young patients affected by IEMRDs present a high rate of clinical complications. Although their proxy (parent)-reported QoL was negatively impacted, their self-reported QoL was variably impacted (both positively and negatively). These results may inform counseling for those who care for affected patients and their families.
Although there has been increasing recognition of the occurrence of non-epileptic involuntary movements in developmental and epileptic encephalopathies (DEEs), the spectrum of dystonic presentations ...associated with these conditions remains poorly described. We sought to expand the catalogue of dystonia-predominant phenotypes in monogenic DEEs, building on the recently introduced concept of an epilepsy-movement disorder spectrum.
Cases were identified from a whole-exome-sequenced cohort of 45 pediatric index patients with complex dystonia (67% sequenced as parent-child trios). Review of molecular findings in DEE-associated genes was performed. For five individuals with identified DEE-causing variants, detailed information about presenting phenotypic features and the natural history of disease was obtained.
De-novo pathogenic and likely pathogenic missense variants in GABRA1, GABBR2, GNAO1, and FOXG1 gave rise to infantile-onset persistent and paroxysmal dystonic manifestations, beginning in the limb or truncal musculature and progressing gradually to a generalized state. Coexisting, less prominent movement-disorder symptoms were observed and included myoclonic, ballistic, and stereotypic abnormal movements as well as choreoathetosis. Dystonia dominated over epileptic neurodevelopmental comorbidities in all four subjects and represented the primary indication for molecular genetic analysis. We also report the unusual case of an adult female patient with dystonia, tremor, and mild learning disability who was found to harbor a pathogenic frameshift variant in MECP2.
Dystonia can be a leading clinical manifestation in different DEEs. A monogenic basis of disease should be considered on the association of dystonia and developmental delay-epilepsy presentations, justifying a molecular screening for variants in DEE-associated genes.
•Epilepsy and non-epileptic abnormal movements can co-exist.•Five of 45 pediatric dystonia patients had variants in developmental and epileptic encephalopathy-related genes.•Mutant cases had complex dystonia but only minimal epileptic comorbidity.•Epilepsy and dystonia can form a phenotypical continuum within the category of neurodevelopmental disorders.•Epilepsy-related genes should be considered in genetic screening panels for dystonia.
Schizophrenia spectrum disorders are presented on 1% of subjects over general population. Organic pathologies prevalence in schizophrenia spectrum patients is not well determined, and it is probably ...underestimated. In the present update review, we are going to highlight seven treatable neurometabolic diseases (NMD) associated to sub-clinic neurological symptoms. It is not infrequent to witness the absence of any clinical neurological signs going along with the NMD. Psychiatric symptoms may be the only clinical alarm that can guide physicians to an acute diagnosis. This is why it is a challenging pathology, defying our clinical accuracy as psychiatrist or any other practitioners confronted to this population. Hereby we are going to expose a literature review and comprehensive tables in order to present in a glance the essential clinical features of disorders of homocysteine metabolism, urea cycle disorders, Niemann-Pick disease type C, acute porphyria, cerebrotendinous-xanthomatosis. These conditions are sensible to major improvement strongly correlated to the accuracy of diagnosis. Literature analysis led us to propose a comprehensive list of atypical psychiatric symptoms including highly predominant visual hallucinations, compared to auditory ones, as well as confusion, catatonia or progressive cognitive decline. We highlight the importance of considering antipsychotic treatment resistance as a crucial sign leading to suspect an organic factor beneath the psychiatric features.
Objective
Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic ...encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed.
Methods
Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants.
Results
Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve AUC = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5μmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model.
Interpretation
This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292–303
A twelve years-old girl was admitted at the pediatric emergency unit for a severe pleuro-pneumopathy. She had a long history of recurrent infections in a complex neurological context. Since birth, ...she had suffered from an epileptic encephalopathy with West syndrome, severe microcephaly and spastic tetraplegia. Her neurological development was extremely impaired: she was not able to neither hold her head nor develop any voluntary hand use. Moreover, she had a precocious puberty and a progressive worsening of her neurological status. She is bedridden, has very poor visual contact and does not speak.
Brain magnetic resonance imaging (MRI) examination has evidenced a severe microcephaly, without gyral anomalies, cerebral atrophy predominating in the frontal lobes, hypoplasia of the corpus callosum and dysmyelination.
Her older sister and parents are healthy and there is no history of consanguinity in the family.
During the infection mentioned above, the only anomaly at complete blood count (CBC) was an excess of monocytes. Yet, and although the CBC instrument had not indicated any alarm for neutrophils, abnormal granules were observed microscopically in polymorphonuclears on the blood smear (fig. 1). The coarse and purplish granules were toluidine-negative, myeloperoxidase-positive and only present in the polymorphonuclear lineage. The large vacuoles in these cells, also seen in monocytes, are related to the infectious condition of the patient in this context of pleuro-pneumopathy. There was no anomaly of the lymphocytes, and specifically no image recalling storage disease.
Although previous CBC had not led to the identification of these granules, they were systematically investigated for, at high magnification, afterwards, always observed but seemed to increase during each infectious episode. Their appearance suggests a coalescence of smaller granules during infection.
A bone marrow aspiration was performed as the patient underwent surgery for severe scoliosis, at distance from any infectious episode. Abnormal granules were present at all stages of neutrophil maturation (fig. 2).
Nobody in the family presents these abnormal granules. Yet, investigations were performed in search of a congenital syndrome or storage disease: metabolic balance, amino acids chromatography in blood and urine, functional analyses of polymorphonuclears, karyotype, CGH array. No anomaly was disclosed. A skin biopsy looking for inclusions allowed to exclude lipofuscinose. Several other investigations were performed which excluded a lysosomal storage disease.
A whole exome analysis was then decided for the child, parents and sister after obtaining informed consent from the parents. This allowed to discover mutations on both alleles ofthe WDR81 gene in the propositus: a deletion leading to a frame shift in exon 3 and a substitution generating a missense in exon 9 (c.3820_3835del p.Pro1274Thrfs*56 and c.5453G>T p.Gly1818Val respectively). The c.3820_3835del deletion was inherited by the father and the c.5453G>T mutation was inherited by the mother.
The mutations were confirmed by Sanger sequencing and segregated with the expected pattern of autosomal-recessive inheritance in all available family members.
This gene has previously been shown to be associated with cerebral ataxia, intellectual disability and quadrupedal locomotion in patients with homozygous mutations in consanguineous families. Moreover, a murine model with mutation of this gene showed tremor and ataxic gait. Expression of WDR81 was found in neuron of central nervous system included Purkinje cells, photoreceptor cells. All these aspects are consistent with the clinical features of the patient, the severity of her disease being possibly related to the fact that both alleles of the WDR81 gene carry a different mutation.
This also suggests that the double genetic defect observed in the WDR81 in this child is responsible for the peculiar granules appearing early during myeloid maturation. Interestingly, the WDR81 gene contains a BEACH domain on its N terminal portion. This domain was described in the BEIGE protein and the highly homologous CHS protein which are involved in Chediak-Higashi syndromes. Although the patient has none of the phenotypic nor immune characteristics of a Chediak-Higashi syndrome, it is highly likely that involvement of the WDR81 gene is responsible for the formation of such pseudo Chediak abnormal granules.
Display omitted Display omitted
No relevant conflicts of interest to declare.
This study aims to define the phenotypic and molecular spectrum of the two clinical forms of β-galactosidase (β-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type ...B, MPSIVB).
Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed.
The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the
gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group.
This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.
Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy that can occur in otherwise healthy children after common viral infections such as influenza and parainfluenza. Most ANE ...is sporadic and nonrecurrent (isolated ANE). However, we identified a 7 Mb interval containing a susceptibility locus (ANE1) in a family segregating recurrent ANE as an incompletely penetrant, autosomal-dominant trait. We now report that all affected individuals and obligate carriers in this family are heterozygous for a missense mutation (c.1880C→T, p.Thr585Met) in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2). To determine whether this mutation is the susceptibility allele, we screened controls and other patients with ANE who are unrelated to the index family. Patients from 9 of 15 additional kindreds with familial or recurrent ANE had the identical mutation. It arose de novo in two families and independently in several other families. Two other patients with familial ANE had different RANBP2 missense mutations that altered conserved residues. None of the three RANBP2 missense mutations were found in 19 patients with isolated ANE or in unaffected controls. We conclude that missense mutations in RANBP2 are susceptibility alleles for familial and recurrent cases of ANE.
PDF
