The effect of galsulfase enzyme replacement therapy on the growth of patients with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

Mucopolysaccharidosis (MPS) VI is an autosomal recessive lysosomal storage disorder arising from deficient activity of N-acetylgalactosamine-4-sulfatase (arylsulfatase B) and subsequent intracellular accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin-4-sulfate. Manifestations are multi-systemic and include skeletal abnormalities such as dysostosis multiplex and short stature. Reference height-for-age growth charts for treatment-naïve MPS VI patients have been published for both the slowly and rapidly progressing populations. Categorization of disease progression for these charts was based on urinary GAG (uGAG) level; high (>200µg/mg creatinine) levels identified subjects as rapidly progressing. Height data for 141 patients who began galsulfase treatment by the age of 18years were collected and stratified by baseline uGAG level and age at ERT initiation in 3-year increments. The reference MPS VI growth charts were used to calculate change in Z-score from pre-treatment baseline to last follow-up. Among patients with high baseline uGAG levels, galsulfase ERT was associated with an increase in Z-score for those beginning treatment at 0-3, >3-6, >6-9, >9-12, and >12-15years of age (p<0.05). Increases in Z-score were not detected for patients who began treatment between 15 and 18years of age, nor for patients with low (≤200µg/mg creatinine) baseline uGAG levels, regardless of age at treatment initiation. The largest positive deviation from untreated reference populations was seen in the high uGAG excretion groups who began treatment by 6years of age, suggesting an age- and severity-dependent impact of galsulfase ERT on growth.

A case of fatal Type I congenital disorders of glycosylation (CDG I) associated with low dehydrodolichol diphosphate synthase (DHDDS) activity.

BACKGROUND: Type I congenital disorders of glycosylation (CDG-I) are mostly complex multisystemic diseases associated with hypoglycosylated serum glycoproteins. A subgroup harbour mutations in genes necessary for the biosynthesis of the dolichol-linked oligosaccharide (DLO) precursor that is essential for protein N-glycosylation. Here, our objective was to identify the molecular origins of disease in such a CDG-Ix patient presenting with axial hypotonia, peripheral hypertonia, enlarged liver, micropenis, cryptorchidism and sensorineural deafness associated with hypo glycosylated serum glycoproteins. RESULTS: Targeted sequencing of DNA revealed a splice site mutation in intron 5 and a non-sense mutation in exon 4 of the dehydrodolichol diphosphate synthase gene (DHDDS). Skin biopsy fibroblasts derived from the patient revealed ~20 % residual DHDDS mRNA, ~35 % residual DHDDS activity, reduced dolichol-phosphate, truncated DLO and N-glycans, and an increased ratio of [2-(3)H]mannose labeled glycoprotein to [2-(3)H]mannose labeled DLO. Predicted truncated DHDDS transcripts did not complement rer2-deficient yeast. SiRNA-mediated down-regulation of DHDDS in human hepatocellular carcinoma HepG2 cells largely mirrored the biochemical phenotype of cells from the patient. The patient also harboured the homozygous ALG6(F304S) variant, which does not cause CDG but has been reported to be more frequent in PMM2-CDG patients with severe/fatal disease than in those with moderate presentations. WES did not reveal other strong candidate causal genes. CONCLUSIONS: We describe a patient presenting with severe multisystem disease associated with DHDDS deficiency. As retinitis pigmentosa is the only clinical sign in previously reported cases, this report broadens the spectrum of phenotypes associated with this condition.

Two new cases of serine deficiency disorders treated with l-serine.

OBJECTIVE AND PATIENTS: We report on two new cases of serine deficiency due respectively to 3-phosphoglycerate dehydrogenase (PHGDH) deficiency (Patient 1) and phosphoserine aminotransferase (PSAT1) deficiency (Patient 2), presenting with congenital microcephaly (<3rd centile at birth) and encephalopathy with spasticity. Patient 1 had also intractable seizures. A treatment with oral l-serine was started at age 4.5 years and 3 months respectively. RESULTS: Serine levels were low in plasma and CSF relative to the reference population, for which we confirm recently redefined intervals based on a larger number of samples. l-Serine treatment led in patient 1 to a significant reduction of seizures after one week of treatment and decrease of electroencephalographic abnormalities within one year. In patient 2 treatment with l-serine led to an improvement of spasticity. However for both patients, l-serine failed to improve substantially head circumference (HC) and neurocognitive development. In a couple related to patient's 2 family, dosage of serine was performed on fetal cord blood when the fetus presented severe microcephaly, showing reduced serine levels at 30 weeks of pregnancy. CONCLUSIONS: l-Serine treatment in patients with 2 different serine synthesis defects, led to a significant reduction of seizures and an improvement of spasticity, but failed to improve substantially neurocognitive impairment. Therefore, CSF and plasma serine levels should be measured in all cases of severe microcephaly at birth to screen for serine deficiency, as prompt treatment with l-serine may significantly impact the outcome of the disease. Reduced serine levels in fetal cord blood may also be diagnostic as early as 30 weeks of pregnancy.

Early and late complications after liver transplantation for propionic acidemia in children: a two centers study.

Propionic acidemia (PA) is a severe metabolic disorder with cardiac and neurologic complications and a poor quality of life. Liver transplantation (LT) was thus proposed in PA to increase enzyme activity. We studied retrospectively LT in PA in two European centers. Twelve patients underwent 17 LTs between 1991 and 2013. They developed severe, unusual and unexpected complications, with high mortality (58%). When present, the cardiomyopathy resolved and no acute metabolic decompensation occurred allowing dietary relaxation. Renal failure was present in half of the patients before LT and worsened in all of them. We suggest that cardiac and renal functions should be assessed before LT and monitored closely afterward. A renal sparing immunosuppression should be used. We speculate that some complications may be related to accumulated toxicity of the disease and that earlier LT could prevent some of these consequences. As kidney transplantation has been performed successfully in methylmalonic acidemia, a metabolic disease in the same biochemical pathway, the choice of the organ to transplant could be further discussed.

[Natural history of Morquio A disease]. / Histoire naturelle de la mucopolysaccharidose IV de type A (maladie de Morquio A).

Type IV mucopolysaccharidosis (Morquio A syndrome; MPS IVA; OMIM 253000), is a multisystemic, severe and very disabling disease, also life-threatening; MPS IVA is due to a deficiency of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), a lysosomal enzyme responsible for the degradation of keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The disease is characterized by respiratory, pulmonary manifestations and also causes bone involvement with progressive spondyloepimetaphyseal degradation and mild and late-onset ophthalmologic, hearing and cardiac complications. These manifestations progressively impair the patients' physical mobility. Severe forms of the disease, diagnosed before the age of 1 year, can be distinguished from intermediary (diagnosed between 1 and 5 years old) and attenuated disease, diagnosed after the age of 5 years (occasionally far later). The main signs are bone deformities namely pectus carinatum, kyphoscoliosis and genu valgum, with early flattening of the growth curve, leading rapidly to almost complete growth arrest. Patients have normal cognitive development. The radiological signs are relatively specific with, in particular, platyspondyly, shortening of the long bones and characteristic pelvic changes. The diagnosis is suggested by elevated urinary GAGs level and profile, and is confirmed by GALNS enzymatic studies on molecular testing. Genetic counseling is important in this autosomal recessive disorder and enzymatic and/or molecular testing can be offered for prenatal diagnosis. Management is mostly symptomatic, based on early detection and orthopedic correction of spine and lower limb deformities, ENT and respiratory management and psychological, social and educational support for the child and his/her family.

Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations.

Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.

[Aspect of brain MRI in mitochondrial respiratory chain deficiency. A diagnostic algorithm of the most common mitochondrial genetic mutations]. / Aspect en IRM cérébrale des maladies mitochondriales. Algorithme décisionnel des maladies mitochondriales les plus fréquentes.

Mitochondrial diseases are due to deficiency of the respiratory chain and are characterized by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Some clinical presentations are highly suggestive of given gene mutations, allowing rapid genetic diagnosis. However, owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is frequently difficult and genotype/phenotype correlations remain elusive. For this reason, brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we report the most frequent neuroradiological signs in mitochondrial respiratory chain deficiency and we propose a diagnostic algorithm based on neuroimaging features, so as to direct molecular genetic tests in patients at risk of mitochondrial respiratory chain deficiency. This algorithm is based on the careful analysis of five areas on brain MRI: (1) basal ganglia (hyperintensities on T2 or calcifications); (2) cerebellum (hyperintensities on T2 or atrophy); (3) brainstem (hyperintensities on T2 or atrophy); (4) white matter (leukoencephalopathy); (5) cortex (sub-tentorial atrophy); (6) stroke-like episodes. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests.

[Hurler syndrome: early diagnosis and treatment]. / Syndrome de Hurler : diagnostic et prise en charge précoces.

Hurler syndrome, the most severe form of mucopolysaccharidosis type I (MPS I), is a rare lysosomal storage disease. The overall incidence of MPS I is 0.99-1.99/100,000 live births. Accumulation of glycosaminoglycans causes the progressive dysfunction of multiple organs. We report the case of a 3-week-old newborn who was hospitalized in the Neonatal Intensive Care Unit for feeding problems. Coarse facial features and gingival hypertrophy, associated with axial hypotonia, upper airway obstruction, and moderate hepatomegaly, led to the early diagnosis of MPS I at 3 weeks of age and was confirmed by an abnormally elevated amount of dermatan and heparan sulphate in the urine and complete deficiency of alpha-L-iduronidase lysosomal enzyme activity. The child was homozygous for the p.W402X mutation, located on chromosome 4p16.3 of the alpha-L-iduronidase (IDUA) gene. The clinical condition gradually deteriorated until the age of 4 months, with thoracic and lumbar dysostoses, glaucoma, cerebral ventricular dilatation and cervical spinal stenosis, dilated cardiomyopathy, and umbilical hernia. Early diagnosis allowed enzyme replacement therapy (iaronidase, Aldurazyme(®), Genzyme) started at the age of 5 months, which provided stabilization of the heart disease, significant regression of rhinologic symptoms, and regression of hepatomegaly. Cord blood hematopoietic stem cell transplantation was performed at 11 months of age, allowing optimal preservation of cognitive development.

Acute psychosis in propionic acidemia: 2 case reports.

Propionic acidemia is an inborn deficiency of propionyl-coenzyme A (CoA) carboxylase activity, which leads to mitochondrial accumulation of propionyl-CoA and its by-products. Neurologic complications are frequent, but only a few cases presenting with psychiatric symptoms have been reported so far. We report 2 cases of children with chronic psychiatric symptoms who presented with an acute psychotic episode as teenagers. Both patients had hallucinations, panic and grossly disorganized behavior, for several weeks to several months. They had signs of moderate metabolic decompensation at the beginning of the episode, although the psychiatric symptoms lasted longer than the metabolic imbalance. We propose that these episodes were at least partially imputable to propionic acidemia. Such episodes require psychiatric examination and antipsychotic treatment, which may have to be adapted in case of cardiomyopathy or long QT syndrome.

Renal transplantation in 4 patients with methylmalonic aciduria: a cell therapy for metabolic disease.

INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut° phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530µmol/L versus 240µmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible.

Treatment of acute decompensation of maple syrup urine disease in adult patients with a new parenteral amino-acid mixture.

BACKGROUND: Acute decompensation of maple syrup urine disease (MSUD) is usually treated by enteral feeding with an amino-acid mixture without leucine (Leu), valine or isoleucine. However, its administration is ineffective in cases of gastric intolerance and some adult patients refuse enteral feeding via a nasogastric tube. We developed a new parenteral amino-acid mixture for patients with MSUD. METHODS: Seventeen decompensation episodes in four adult patients with MSUD treated with a parenteral amino-acid mixture (group P) were compared to 18 previous episodes in the same patients treated by enteral feeding (group E). RESULTS: The mean Leu concentration at presentation was similar in the groups P and E (1196.9 µmol/L and 1212.2 µmol/L, respectively). The mean decrease in the Leu concentration during the first 3 days of hospitalisation was significantly higher in group P than group E (p = 0.0026); there were no side effects. The mean duration of hospitalisation was similar (4 vs. 4.5 days, p = NS). No patient in group P deteriorated whereas one patient in group E required dialysis. CONCLUSION: This new parenteral amino-acid mixture is safe and allows efficient Leu concentration decrease during acute MSUD decompensation episodes in adults. Its use avoids the need for nasogastric tube insertion.

[Prenatal symptoms and diagnosis of inherited metabolic diseases]. / Maladies héréditaires du métabolisme : signes anténatals et diagnostic biologique.

Inherited metabolic diseases are mostly due to enzyme deficiency in one of numerous metabolic pathways, leading to absence of a compound downstream from and the accumulation of a compound upstream from the deficient metabolite(s). Diseases of intoxication by proteins (aminoacidopathies, organic acidurias, urea cycle defects) and by sugars (galactosemia, fructosemia) usually do not give prenatal symptoms since mothers protect their fetuses from pathological metabolite accumulation. A well-known exception is hypoplasia of corpus callosum, as is sometimes observed in nonketotic hyperglycinemia and sulfite oxidase deficiency. Conversely, women with phenylketonuria "poison" their fetus if they are not treated (spontaneous abortions, intrauterine growth restriction [IUGR], cardiac malformations, and brain disease). Amino acid synthesis defects can lead to prenatal symptoms: microcephaly in serine deficiency (detectable by amino acid analysis in fetal cord blood), and brain malformations in glutamine synthetase deficiency. Impaired folate metabolism is involved in a large fraction of neurodevelopmental defects referred to as spina bifida, yet the underlying genetic component(s) are largely unknown. Energy metabolism diseases caused by defects in the synthesis or utilization of relevant metabolites lead to organ dysfunctions or malformations, but prenatal diagnosis is usually impossible unless genetic analysis can rely on a previously affected child in the family. A somewhat intermediate condition is defects of mitochondrial beta-oxidation of fatty acids, as they may sometimes be symptomatic prenatally (notably the HELLP syndrome or other presentations), and in this case, organic acid and acylcarnitine analysis in amniotic fluid can be informative in the absence of an index case. In contrast, complex molecule diseases commonly give prenatal symptoms that may permit the diagnosis even in the absence of index cases: hydrops fetalis and skeletal anomalies in lysosomal storage diseases, hydrops fetalis in congenital disorders of glycosylation (CDG) and transaldolase deficiency, brain malformations in O-glycosylation defects, brain malformations, kidney cysts and skeletal anomalies in peroxysomal diseases (Zellweger syndrome), syndactyly, genitalia malformations, and IUGR in Smith-Lemli-Opitz (SLO) syndrome. Although many metabolic disorders show biochemical abnormalities during fetal development that are informative for prenatal diagnosis, only a fraction of them are clinically/sonographically symptomatic before birth, thus allowing for prenatal diagnosis in the absence of an index case, i.e., serine deficiency, some fatty acid beta-oxidation defects, transaldolase deficiency, lysosomal diseases, CDG, Zellweger syndrome, and SLO syndrome.

[Enzyme replacement therapy for lysosomal storage disorders]. / Le traitement par enzymothérapie des maladies lysosomales.

In the last years, much progress has been achieved in the treatment of lysosomal storage disorders. Until recently only symptomatic treatment was available for the affected patients. Progressively enzyme replacement treatments have been developed for several diseases, namely Gaucher disease, Fabry disease, mucopolysaccharidoses type I, II and VI and Pompe disease. In this review we will summarize the efficacy and safety of these treatments and describe new therapeutic trials for other lysosomal storage disorders or perspectives in the use of currently available treatments.

A common pattern of brain MRI imaging in mitochondrial diseases with complex I deficiency.

OBJECTIVE: To identify a consistent pattern of brain MRI imaging in primary complex I deficiency. Complex I deficiency, a major cause of respiratory chain dysfunction, accounts for various clinical presentations, including Leigh syndrome. Human complex I comprises seven core subunits encoded by mitochondrial DNA (mtDNA) and 38 core subunits encoded by nuclear DNA (nDNA). Moreover, its assembly requires six known and many unknown assembly factors. To date, no correlation between genotypes and brain MRI phenotypes has been found in complex I deficiencies. DESIGN AND SUBJECTS: The brain MRIs of 30 patients carrying known mutation(s) in genes involved in complex I were retrospectively collected and compared with the brain MRIs of 11 patients carrying known mutations in genes involved in the pyruvate dehydrogenase (PDH) complex as well as 10 patients with MT-TL1 mutations. RESULTS: All complex I deficient patients showed bilateral brainstem lesions (30/30) and 77% (23/30) showed anomalies of the putamen. Supratentorial stroke-like lesions were only observed in complex I deficient patients carrying mtDNA mutations (8/19) and necrotising leucoencephalopathy in patients with nDNA mutations (4/5). Conversely, the isolated stroke-like images observed in patients with MT-TL1 mutations, or the corpus callosum malformations observed in PDH deficient patients, were never observed in complex I deficient patients. CONCLUSION: A common pattern of brain MRI imaging was identified with abnormal signal intensities in brainstem and subtentorial nuclei with lactate peak as a clue of complex I deficiency. Combining clinico-biochemical data with brain imaging may therefore help orient genetic studies in complex I deficiency.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic ß-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.

Posterior fossa imaging in 158 children with ataxia.

OBJECTIFS: To propose a MRI cerebellar algorithm that may be applied to guide genetic/malformative or biochemical investigations for patients with cerebellar ataxia. PATIENTS AND METHODS: Cerebral MRI of 158 patients with cerebellar ataxia and no supratentorial abnormality were examined according to a new categorization system based on posterior fossa imaging. The clinical and radiological findings were confronted to biochemical and/or genetic results using the MR cerebellar algorithm. Seven groups of cerebellar MRI pattern were described: vermian dysgenesis (n=27), cerebellar hypoplasia (n=15), hemispheric cerebellar dysgenesis (n=6), unilateral hemispheric atrophy (n=5), global cerebellar atrophy (n=84), signal abnormalities (n=11) and normal MRI (n=10). Cerebellar hypoplasia, vermian dysgenesis and hemispheric cerebellar dysgenesis groups were classified as malformative disorders. Global atrophy and signal abnormality groups were classified as metabolic disorders. RESULTS: In the vermian dysgenesis group, a specific genetic diagnosis was obtained in eight children (8/27) and all of the mutated genes (AHI1 (JBS3), CEP290 (JBS5), TMEM67 (JBS6), and RPGRIP1L (JBS7)) are involved in primary cilia function. In the group of pontocerebellar hypoplasia specific genetic diagnosis was obtained in one patient (PCH2) (1/15). Thus, nine of 42 children classified as malformative disorder had a molecular diagnosis. Global atrophy and signal abnormality groups were classified as metabolic disorders, specific biochemical was obtained in 46/95 children. In global atrophy group, respiratory chain deficiency was diagnosed in 18 children (18/84). In 21 children a congenital disorders of glycosylation type 1a (CDG Ia) was diagnosed (21/84) and infantile neuroaxonale dystrophy (INAD) was diagnosed in one child. In signal abnormalities group, specific biochemical diagnosis was obtained in six out of 11 children, five children with respiratory chain deficiency and one child with sulphite oxidase deficiency. In hemispheric cerebellar dysgenesis and normal MRI groups, no biological diagnosis was found for any of the patients. In the group of unilateral hemispheric atrophy, we hypothesized a clastic prenatal injury. CONCLUSION: The proposed MR cerebellar algorithm was useful to guide genetic/malformative or biochemical investigations, allowing an etiological diagnosis in 55 children.

Cognitive and neuroradiological improvement in three patients with attenuated MPS I treated by laronidase.

Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.