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1.
Can J Neurol Sci ; 46(6): 717-726, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31387656

RESUMO

BACKGROUND: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. METHODS: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. RESULTS: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. CONCLUSIONS: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.

2.
Eur J Hum Genet ; 27(10): 1611-1618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31278393

RESUMO

The developmental and epileptic encephalopathies (DEE) are a heterogeneous group of chronic encephalopathies frequently associated with rare de novo nonsynonymous coding variants in neuronally expressed genes. Here, we describe eight probands with a DEE phenotype comprising intellectual disability, epilepsy, and hypotonia. Exome trio analysis showed de novo variants in TRPM3, encoding a brain-expressed transient receptor potential channel, in each. Seven probands were identically heterozygous for a recurrent substitution, p.(Val837Met), in TRPM3's S4-S5 linker region, a conserved domain proposed to undergo conformational change during gated channel opening. The eighth individual was heterozygous for a proline substitution, p.(Pro937Gln), at the boundary between TRPM3's flexible pore-forming loop and an adjacent alpha-helix. General-population truncating variants and microdeletions occur throughout TRPM3, suggesting a pathomechanism other than simple haploinsufficiency. We conclude that de novo variants in TRPM3 are a cause of intellectual disability and epilepsy.

3.
Brain ; 142(3): 542-559, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668673

RESUMO

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

4.
Am J Med Genet A ; 2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30244534

RESUMO

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.

5.
Mol Genet Metab ; 125(3): 281-291, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30177229

RESUMO

An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia. In this report, we present an additional 15 individuals from 12 families who are mostly Arabs homozygous for the pathogenic variant Y144C, which is associated with the more severe early onset phenotype. The total number of unique pathogenic FARS2 variants known to date is 21 including three different partial gene deletions reported in four individuals. Except for the large deletions, all variants but two (one in-frame deletion of one amino acid and one splice-site variant) are missense. All large deletions and the single splice-site variant are in trans with a missense variant. This suggests that complete loss of function may be incompatible with life. In this report, we also review structural, functional, and evolutionary significance of select FARS2 pathogenic variants reported here.

6.
Mol Genet Metab ; 123(3): 309-316, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29269105

RESUMO

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.

7.
Am J Med Genet B Neuropsychiatr Genet ; 177(1): 101-109, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29152901

RESUMO

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.


Assuntos
Síndrome do Hamartoma Múltiplo/fisiopatologia , Leucoencefalopatias/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Adolescente , Adulto , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento , Feminino , Síndrome do Hamartoma Múltiplo/genética , Humanos , Inteligência , Leucoencefalopatias/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fenótipo , Substância Branca/patologia
8.
Eur J Hum Genet ; 25(9): 1049-1054, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28635952

RESUMO

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P2] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P2 synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.


Assuntos
Displasia Cleidocraniana/genética , Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Proteínas de Membrana/genética , Micrognatismo/genética , Mutação , Alelos , Células Cultivadas , Displasia Cleidocraniana/diagnóstico , Displasia Ectodérmica/diagnóstico , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Recém-Nascido , Inositol/metabolismo , Deformidades Congênitas dos Membros/diagnóstico , Proteínas de Membrana/metabolismo , Micrognatismo/diagnóstico , Fenótipo , Ftalimidas/farmacologia , Quinolinas/farmacologia , Vacúolos/metabolismo
9.
Neuropediatrics ; 48(3): 166-184, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28561207

RESUMO

We investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi-Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64-25.71) compared with controls (median: 0.93, IQR: 0.57-1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Interferon Tipo I/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Proteínas de Ligação a RNA/genética , Adolescente , Adulto , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Biomarcadores/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Fenótipo , Adulto Jovem
10.
CMAJ ; 188(11): E254-60, 2016 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-27241786

RESUMO

BACKGROUND: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. METHODS: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. RESULTS: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. INTERPRETATION: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.


Assuntos
Estudos de Associação Genética/métodos , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Unidades de Terapia Intensiva Neonatal , Doenças Raras/diagnóstico , Doenças Raras/genética , Feminino , Humanos , Recém-Nascido , Masculino , Mutação , Ontário , Projetos Piloto , Estudos Prospectivos , Estudos Retrospectivos
11.
JIMD Rep ; 30: 73-79, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27306203

RESUMO

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient's organic acids confirmed the D- and L-2-hydroxyglutaric aciduria typical of DL-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders. One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.

12.
Eur J Hum Genet ; 24(7): 1084-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26604000

RESUMO

Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia Resistente a Medicamentos/genética , GTP Fosfo-Hidrolases/genética , Proteínas Associadas aos Microtúbulos/genética , Dinâmica Mitocondrial/genética , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto , Células Cultivadas , Criança , Deficiências do Desenvolvimento/patologia , Epilepsia Resistente a Medicamentos/patologia , Exoma , Fibroblastos/ultraestrutura , Humanos , Masculino , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/ultraestrutura , Músculo Esquelético/ultraestrutura , Síndrome
13.
JIMD Rep ; 27: 1-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26404457

RESUMO

Mutations of FBXL4, which encodes an orphan mitochondrial F-box protein, are a recently identified cause of encephalomyopathic mtDNA depletion. Here, we describe the detailed clinical and biochemical phenotype of a neonate presenting with hyperlactatemia, leukoencephalopathy, arrhythmias, pulmonary hypertension, dysmorphic features, and lymphopenia. Next-generation sequencing in the proband identified a homozygous frameshift, c.1641_1642delTG, in FBXL4, with a surrounding block of SNP marker homozygosity identified by microarray. Muscle biopsy showed a paucity of mitochondria with ultrastructural abnormalities, mitochondrial DNA depletion, and profound deficiency of all respiratory chain complexes. Cell-based mitochondrial phenotyping in fibroblasts showed mitochondrial fragmentation, decreased basal and maximal respiration, absence of ATP-linked respiratory and leak capacity, impaired survival under obligate aerobic respiration, and reduced mitochondrial inner membrane potential, with relative sparing of mitochondrial mass. Cultured fibroblasts from the patient exhibited a more oxidized glutathione ratio, consistent with altered cellular redox poise. High-resolution respirometry of permeabilized muscle fibers showed marked deficiency of oxidative phosphorylation using a variety of mitochondrial energy substrates and inhibitors. This constitutes the fourth and most detailed report of FBXL4 deficiency to date. In light of our patient's clinical findings and genotype (homozygous frameshift), this phenotype likely represents the severe end of the FBXL4 clinical spectrum.

14.
CMAJ ; 187(2): 102-7, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25452324

RESUMO

BACKGROUND: Congenital sucrase-isomaltase deficiency is a rare hereditary cause of chronic diarrhea in children. People with this condition lack the intestinal brush-border enzyme required for digestion of di- and oligosaccharides, including sucrose and isomaltose, leading to malabsorption. Although the condition is known to be highly prevalent (about 5%-10%) in several Inuit populations, the genetic basis for this has not been described. We sought to identify a common mutation for congenital sucrase-isomaltase deficiency in the Inuit population. METHODS: We sequenced the sucrase-isomaltase gene, SI, in a single Inuit proband with congenital sucrase-isomaltase deficiency who had severe fermentative diarrhea and failure to thrive. We then genotyped a further 128 anonymized Inuit controls from a variety of locales in the Canadian Arctic to assess for a possible founder effect. RESULTS: In the proband, we identified a novel, homozygous frameshift mutation, c.273_274delAG (p.Gly92Leufs*8), predicted to result in complete absence of a functional protein product. This change was very common among the Inuit controls, with an observed allele frequency of 17.2% (95% confidence interval [CI] 12.6%-21.8%). The predicted Hardy-Weinberg prevalence of congenital sucrase-isomaltase deficiency in Inuit people, based on this single founder allele, is 3.0% (95% CI 1.4%-4.5%), which is comparable with previous estimates. INTERPRETATION: We found a common mutation, SI c.273_274delAG, to be responsible for the high prevalence of congenital sucrase-isomaltase deficiency among Inuit people. Targeted mutation testing for this allele should afford a simple and minimally invasive means of diagnosing this condition in Inuit patients with chronic diarrhea.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos/etnologia , Erros Inatos do Metabolismo dos Carboidratos/genética , Efeito Fundador , Inuítes/genética , Mutação/genética , Complexo Sacarase-Isomaltase/deficiência , Complexo Sacarase-Isomaltase/genética , Canadá/epidemiologia , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Recém-Nascido
16.
Neurology ; 82(11): 963-8, 2014 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-24553428

RESUMO

OBJECTIVE: To determine the causative genetic lesion in 3 adult siblings with a slowly progressive, juvenile-onset phenotype comprising cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy, and (in 2 of 3 probands) supratentorial white matter changes, in whom numerous prior investigations were nondiagnostic. METHODS: The patients' initial clinical assessment included history and physical examination, cranial MRI, and nerve conduction studies. We performed whole-exome sequencing of all 3 probands, followed by variant annotation and selection of rare, shared, recessive coding changes to identify the gene responsible. We next performed a panel of peroxisomal investigations in blood and cultured fibroblasts, including assessment of D-bifunctional protein (DBP) stability and activity by immunoblot and enzymologic methods, respectively. RESULTS: Exome sequencing identified compound heterozygous mutations in HSD17B4, encoding peroxisomal DBP, in all 3 probands. Both identified mutations alter a conserved residue within the active site of DBP's enoyl-CoA hydratase domain. Routine peroxisomal screening tests, including very long-chain fatty acids and phytanic acid, were normal. DBP enzymatic activity was markedly reduced. CONCLUSION: Exome sequencing provides a powerful and elegant tool in the specific diagnosis of "mild" or "atypical" neurometabolic disorders. Given the broad differential diagnosis and the absence of detectable biochemical abnormalities in blood, molecular testing of HSD17B4 should be considered as a first-line investigation in patients with compatible features.


Assuntos
Proteína Multifuncional do Peroxissomo-2/deficiência , Deficiência de Proteína/genética , Deficiência de Proteína/metabolismo , Adulto , Células Cultivadas , Análise Mutacional de DNA , Exoma , Ácidos Graxos/sangue , Ácidos Graxos/líquido cefalorraquidiano , Feminino , Fibroblastos/metabolismo , Humanos , Masculino , Irmãos
17.
JIMD Rep ; 12: 79-84, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23900835

RESUMO

Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.

18.
JIMD Rep ; 14: 11-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24222494

RESUMO

Danon disease is a rare X-linked disorder comprising hypertrophic cardiomyopathy, skeletal myopathy, intellectual disability, and retinopathy; mutations of the lysosome-associated membrane protein gene LAMP2 are responsible. Most affected persons exhibit "private" point mutations; small locus rearrangements have recently been reported in four cases. Here, we describe the clinical, pathologic, and molecular features of a male proband and his affected mother with Danon disease and a small LAMP2 microduplication. The proband presented at age 12 years with exercise intolerance, hypertrophic cardiomyopathy, and increased creatine kinase. Endomyocardial biopsy findings were nonspecific, showing myocyte hypertrophy and reactive mitochondrial changes. Quadriceps muscle biopsy demonstrated the characteristic autophagic vacuoles with sarcolemma-like features. LAMP2 tissue immunostaining was absent; however, LAMP2 sequencing was normal. Deletion/duplication testing by multiplex ligation-dependent probe amplification (MLPA) assay revealed a 1.5kb microduplication containing LAMP2 exons 4 and 5. RT-PCR studies were consistent with the inclusion of these two duplicated exons in the final spliced transcript, resulting in a frameshift. The proband's mother, who had died following cardiac transplantation due to suspected myocarditis at age 35, was reviewed and was shown to be affected upon immunostaining of banked myocardial tissue. This case constitutes the second report of a pathogenic microduplication in Danon disease, and illustrates a number of potential diagnostic pitfalls. Firstly, given the imperfect sensitivity of LAMP2 sequencing, tissue immunostaining and/or MLPA should be considered as a diagnostic adjunct in the workup for this disorder. Secondly, the pathological findings in myocardium may be falsely indicative of relatively common conditions such as myocarditis.

19.
Nat Genet ; 44(4): 445-9, S1, 2012 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-22366787

RESUMO

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.


Assuntos
Proteínas Cromossômicas não Histona/genética , Deformidades Congênitas do Pé/genética , Hipotricose/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Facies , Genes Reguladores , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , Alinhamento de Sequência , Análise de Sequência de DNA , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Transcrição Genética , Adulto Jovem
20.
Am J Hum Genet ; 90(2): 369-77, 2012 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-22305528

RESUMO

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.


Assuntos
GTP Fosfo-Hidrolases/genética , Haploinsuficiência/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/genética , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Exoma , Feminino , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação/genética , Estrutura Terciária de Proteína/genética , Processamento de RNA/genética , Spliceossomos/genética
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