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Background and Objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.
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We present the case of a 36-year-old female who was diagnosed at birth with CHI that caused severe hypoglycaemia unresponsive to Diazoxide. Subtotal pancreatectomy was performed at the age of three weeks. Later, histological analysis of her pancreas in a research setting revealed a focal form of CHI. Genetic testing was not available at that time. The patient developed pancreatic exocrine deficiency and insulin-dependent diabetes at the age of 9 years. In 2016, a genetic test revealed a missense heterozygous variant in the ABCC8 gene inherited from her father and classified as having a recessive inheritance. The geneticist concluded that the risk of CHI for her offspring would be low (1/600), making pregnancy favourable. As there was no consanguinity in the family, testing the future father was deemed unnecessary (carrier frequency 1/150 in the general population). The pregnancy occurred spontaneously in 2020 and at a gestational age of 28 weeks, the mother went into premature labour. An emergency C-section was performed in April 2021 resulting in the birth of bichorial bi-amniotic male twins. Following birth, both newborns experienced persistent severe hypoglycaemia which required glucagon treatment and intravenous glucose infusion initially, followed by Diazoxide from day 51 after birth, without satisfactory response. Continuous intravenous Octreotide treatment was introduced on day 72. Due to the recurrence of hypoglycaemia episodes despite reaching maximum doses of Octreotide, from day 92 the treatment was switched to Pasireotide. Genetic tests revealed the same genotypes for both infants: the exon 39 missense variant (c.4716C>A; p.Ser1572Arg) inherited from their mother and a truncating variant in exon 28 (c.3550del; p.Val1184*), inherited from their asymptomatic father. As a result of inheriting two recessive variants of the ABCC8 gene, the children were diagnosed with a diffuse form of CHI, consistent with the diazoxide-unresponsive presentation. This situation is very rare outside consanguinity. This case emphasises the significance of genetic counselling for individuals with a history of rare diseases outside the context of consanguinity, as there is a potential risk of recurrence. Prenatal diagnosis can lead to better outcomes for affected neonates, as well as help families make informed decisions about future pregnancies.
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Hiperinsulinismo Congénito , Humanos , Femenino , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/tratamiento farmacológico , Embarazo , Adulto , Recién Nacido , Receptores de Sulfonilureas/genética , Masculino , Gemelos Dicigóticos/genéticaAsunto(s)
ADN Polimerasa gamma , Imagen por Resonancia Magnética , Mutación , Humanos , ADN Polimerasa gamma/genética , Lactante , Masculino , FemeninoRESUMEN
Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.
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BACKGROUND AND AIMS: Water-soluble vitamins play an essential coenzyme role in the nervous system. Acquired vitamin deficiencies are easily treatable, however, without treatment, they can lead to irreversible complications. This study aimed to provide clinical, laboratory parameters and neuroimaging data on vitamin deficiencies in an attempt to facilitate early diagnosis and prompt supplementation. METHODS: From July 1998 to July 2023, patients at Necker-Enfants-Malades Hospital presenting with acute neurological symptoms attributed to acquired vitamin deficiency were included. Clinical data were extracted from Dr Warehouse database. Neuroimaging, biochemical and electrophysiological data were reviewed. RESULTS: Patients with vitamin B1 deficiency exhibited abnormal eye movements (n = 4/4), fluctuations in consciousness (n = 3/4), and ataxia (n = 3/4). Brain MRI showed alterations of fourth ventricle region (n = 4/4), periaqueductal region (n = 4/4), tectum (n = 3/4), and median thalami (n = 3/4). Patients with vitamin B2 deficiency presented with early onset hypotonia (n = 3/4), hyperlactatemia (n = 4/4), and hyperammonemia (n = 4/4). Plasma acylcarnitines revealed a multiple acyl-coA dehydrogenase deficiency-like profile (n = 4/4). In vitamin B12 deficiency, young children presented with developmental delay (n = 7/7) and older children with proprioceptive ataxia (n = 3/3). Brain MRI revealed atrophy (n = 7/7) and spinal MRI hyperintensity in posterior cervical columns (n = 3/3). Metabolic findings showed elevated methylmalonic acid (n = 6/7) and hyperhomocysteinemia (n = 6/7). Patients with vitamin C deficiency exhibited gait disturbances and muscle weakness (n = 2/2). CONCLUSIONS: Acquired vitamin deficiencies may display reversible clinical symptoms mimicking inherited metabolic disorders. Some situations raise suspicion for diagnosis: concordant clinical presentation, suggestive neuroimaging findings, and/or biochemical evidence. Any acute neurological condition should be treated without waiting for definitive biochemical confirmation.
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Imagen por Resonancia Magnética , Neuroimagen , Humanos , Masculino , Femenino , Preescolar , Neuroimagen/métodos , Lactante , Niño , Avitaminosis/complicaciones , Avitaminosis/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Adolescente , Estudios RetrospectivosRESUMEN
OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.
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Trastornos Congénitos de Glicosilación , Fosfotransferasas (Fosfomutasas) , Accidente Cerebrovascular , Trombosis , Humanos , Niño , Proteína C , Estudios Retrospectivos , Factor XI , Trastornos Congénitos de Glicosilación/patología , Antitrombinas , Hemostasis , HemorragiaRESUMEN
In Infantile Onset Pompe Disease (IOPD), enzyme replacement therapy (ERT) may improve survival, cardiac function, and motor development. However, even with early enzyme replacement therapy, some patients experienced poor response to ERT and abnormal motor milestones that could be due to motor neuron involvement. In this long-term retrospective study, we analyzed concomitant clinical motor outcomes and electroneuromyography (ENMG) findings in patients with IOPD and Juvenile Onset Pompe Disease (JOPD). Twenty-nine pediatric patients were included and 20 surviving were analyzed for neuromotor studies: 12 had IOPD (group 1), 4 had JOPD (group 2) and 4 (group 3) received ERT in the first month of age. Motor nerve conduction studies were mostly normal. Needle EMG performed at diagnosis always indicated the existence of myopathy that responded to ERT. Two IOPD patients (group 1) presenting with mixed motor neuropathy and myopathy displayed a poor outcome and never walked. Two patients became non-walkers (one IOPD patient and one patient of group 3) at respectively 9 and 3 years of age. One JOPD patient is about to lose walking ability. This motor deterioration was associated with the development of a motor neuropathy. Patients older than 10 years of age develop a motor neuropathy. Initial or secondary motor neuron involvement seems to be associated with a poor motor outcome showing that ERT may fail to prevent the accumulation of glycogen in motor neuron. Neurophysiological findings are important to assess severity of motor neuron damage in all Pompe pediatric patients and should be systematically performed.
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BACKGROUND: Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle, but limited data are available regarding the use of citrulline. This study retrospectively reviewed clinical and biological data from patients with UCDs treated with citrulline and/or arginine at a reference center since 1990. The aim was to describe the prescription, impact, and safety of these therapies. Data collection included patient background, treatment details, changes in biochemical parameters (plasma ammonia and amino acids concentrations), decompensations, and patient outcomes. RESULTS: Overall, 79 patients (median age at diagnosis, 0.9 months) received citrulline and/or arginine in combination with a restricted protein diet, most with ornithine transcarbamylase (n = 57, 73%) or carbamoyl phosphate synthetase 1 (n = 15, 19%) deficiencies. Most patients also received ammonium scavengers. Median follow-up was 9.5 years and median exposure to first treatment with arginine + citrulline, citrulline monotherapy, or arginine monotherapy was 5.5, 2.5, or 0.3 years, respectively. During follow-up, arginine or citrulline was administered at least once (as monotherapy or in combination) in the same proportion of patients (86.1%); the overall median duration of exposure was 5.9 years for arginine + citrulline, 3.1 years for citrulline monotherapy, and 0.6 years for arginine monotherapy. The most common switch was from monotherapy to combination therapy (41 of 75 switches, 54.7%). During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05). At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%). Two patients (2.5%) experienced three treatment-related gastrointestinal adverse reactions. CONCLUSIONS: This study underlines the importance of citrulline supplementation, either alone or together with arginine, in the management of patients with UCDs. When a monotherapy is considered, citrulline would be the preferred option in terms of increasing plasma arginine concentrations.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Trastornos Innatos del Ciclo de la Urea , Humanos , Citrulina/uso terapéutico , Amoníaco , Estudios Retrospectivos , Trastornos Innatos del Ciclo de la Urea/tratamiento farmacológico , Arginina/uso terapéutico , Urea/uso terapéuticoRESUMEN
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
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Enfermedades Autoinmunes del Sistema Nervioso , Malformaciones del Sistema Nervioso , Humanos , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/tratamiento farmacológico , Enfermedades Autoinmunes del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/tratamiento farmacológico , Malformaciones del Sistema Nervioso/genética , Transducción de Señal , Pruebas GenéticasRESUMEN
Mutations in the LPIN1 gene constitute a major cause of severe rhabdomyolysis (RM). The TLR9 activation prompted us to treat patients with corticosteroids in acute conditions. In patients with LPIN1 mutations, RM and at-risk situations that can trigger RM have been treated in a uniform manner. Since 2015, these patients have also received intravenous corticosteroids. We retrospectively compared data on hospital stays by corticosteroid-treated patients vs. patients not treated with corticosteroids. Nineteen patients were hospitalized. The median number of admissions per patient was 21 overall and did not differ when comparing the 10 corticosteroid-treated patients with the 9 patients not treated with corticosteroids. Four patients in the non-corticosteroid group died during a RM (mean age at death: 5.6 years). There were no deaths in the corticosteroid group. The two groups did not differ significantly in the number of RM episodes. However, for the six patients who had RM and occasionally been treated with corticosteroids, the median number of RM episodes was significantly lower when intravenous steroids had been administered. The peak plasma creatine kinase level and the area under the curve were or tended to be higher in patients treated with corticosteroids-even after the exclusion of deceased patients or focusing on the period after 2015. The median length of stay (10 days overall) was significantly longer for corticosteroid-treated patients but was similar after the exclusion of deceased patients. The absence of deaths and the higher severity of RM observed among corticosteroid-treated patients could suggest that corticotherapy is associated with greater survival.
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Rabdomiólisis , Humanos , Preescolar , Estudios Retrospectivos , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/inducido químicamente , Glucocorticoides , Enfermedad Aguda , Fosfatidato Fosfatasa/genéticaRESUMEN
CONTEXT: A strictly controlled diet (often involving enteral tube feeding (ETF)) is part of the treatment of many inherited metabolic diseases (IMDs). OBJECTIVE: To describe the use of ETF in a large cohort of patients with IMDs. DESIGN: A retrospective analysis of ETF in patients with urea cycle disorders (UCDs), organic aciduria (OA), maple syrup disease (MSUD), glycogen storage diseases (GSDs) or fatty acid oxidation disorders (FAODs) diagnosed before the age of 12â¯months. SETTING: The reference center for IMDs at Necker Hospital (Paris, France). RESULTS: 190 patients born between January 1991 and August 2017 were being treated for OA (nâ¯=â¯60), UCDs (nâ¯=â¯55), MSUD (nâ¯=â¯32), GSDs (nâ¯=â¯26) or FAODs (nâ¯=â¯17). Ninety-eight of these patients (52%) received ETF (OA subgroup: nâ¯=â¯40 (67%); UCDs: nâ¯=â¯12 (22%); MSUD: nâ¯=â¯9 (28%); GSDs: nâ¯=â¯23 (88%); FAODs: nâ¯=â¯14 (82%)). Indications for ETF were feeding difficulties in 64 (65%) patients, cessation of fasting in 39 (40%), and recurrent metabolic decompensation in 14 (14%). Complications of ETF were recorded in 48% of cases, more frequently with nasogastric tube (NGT) than with gastrostomy. Among patients in whom ETF was withdrawn, the mean duration of ETF was 5.9 (SD: 4.8) years (range: 0.6-19.8â¯years). The duration of ETF was found to vary from one disease subgroup to another (pâ¯=â¯0.051). While the longest median duration was found in the GSD subgroup (6.8â¯years), the shortest one was found in the UCD subgroup (0.9â¯years). CONCLUSION: ETF is an integral part of the dietary management of IMDs. The long duration of ETF and the specific risks of NGT highlights the potential value of gastrostomy.In this study at a French tertiary hospital, we documented the indications, modalities, duration and complications of enteral tube feeding in a cohort of patients with inherited metabolic diseases.
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TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.