ABSTRACT
BACKGROUND: Excellence in Pain Education was the motto of the International Association for the Study of Pain (IASP) Global Year Campaign for 2018. Explaining pain neurobiology to patients is one part of pain education. To assess patient's pain knowledge, the Neurophysiology of Pain Questionnaire (NPQ) has been extensively used internationally. The present study describes the translation, cross-cultural adaptation and psychometric properties of the German version of the NPQ (NPQD). MATERIALS AND METHODS: The questionnaire was translated and adapted following established recommendations. A total of 169 patients and 122 physiotherapists completed the NPQD. The patients also completed the SF12 and the FFbH-R for the purpose of construct validation of the NPQD. Furthermore, 55 patients repeated the NPQD after 10 days. The NPQD was tested for dimensionality, internal consistency, construct validity and test-retest reliability. RESULTS: Internal consistency was αâ¯= 0.52. An exploratory factor analysis revealed four different factors. Therapists did show significantly higher NPQD scores than patients (pâ¯< 0.001) and therapist who have been educated in pain neurophysiology scored significantly higher than therapists without this education (pâ¯< 0.01). Test-retest reliability was high (ICCâ¯= 0.88; 95% CIâ¯= 0.82-0.93). There were no correlations between NPQD and SF12 or FFbH-R indicating construct validity of the NPQD. CONCLUSIONS: The NPQ has been translated and adapted into German. The psychometric properties show satisfactory results and the questionnaire can be recommended for clinicians and researchers alike to assess pain knowledge and changes in pain knowledge after pain education interventions.
Subject(s)
Cross-Cultural Comparison , Pain , Humans , Psychometrics , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.
Subject(s)
Aspartate Carbamoyltransferase/genetics , Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/genetics , Dihydroorotase/genetics , Mutation/genetics , Spasms, Infantile/drug therapy , Spasms, Infantile/genetics , Uridine/therapeutic use , Anemia/complications , Anemia/drug therapy , Anemia/genetics , Brain/diagnostic imaging , Child , Child, Preschool , DNA Mutational Analysis , Developmental Disabilities/complications , Developmental Disabilities/genetics , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Spasms, Infantile/complications , Spasms, Infantile/diagnostic imagingABSTRACT
Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. Main Outcomes: The primary end point was the achievement of motor milestones. Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. Trial Registration: German Clinical Trials Register: DRKS00012699.
Subject(s)
Neonatal Screening , Humans , Neonatal Screening/methods , Infant, Newborn , Female , Male , Infant , Germany , Registries , Muscular Atrophy, Spinal/diagnosis , Pilot Projects , Early DiagnosisABSTRACT
Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.
Subject(s)
Muscular Atrophy, Spinal , Survival of Motor Neuron 2 Protein , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Age of Onset , Austria/epidemiology , Disease Progression , Germany , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/diagnosis , Neonatal Screening , Registries , Retrospective Studies , Survival of Motor Neuron 2 Protein/genetics , SwitzerlandABSTRACT
Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.
ABSTRACT
Mutations in the X-linked E1α subunit of the pyruvate dehydrogenase complex (PHDC) are the most frequent causes of PDHC deficiency. The clinical picture is heterogeneous depending on residual enzyme activity and X-inactivation. We report on a girl who presented at an age of 3 weeks with muscular hypotonia, vomiting, hyperlactatemia, microcephaly, enlarged ventricles, partial agenesis of the corpus callosum, and seizures. PDHA1 sequencing was normal in DNA from blood. In muscle, normal PDHC activity was measured while substrate oxidation rates revealed moderately diminished pyruvate oxidation. Quantitative PCR analysis revealed hemizygosity of the whole PDHA1 gene. Homozygosity mapping and determination of the breakpoint showed a 1.1 million base pair deletion on the X-chromosome including the CDKL5 and PDHA1 genes. The difficulty in the diagnosis of PDHC deficiency is evident: (1) enzyme activity can be normal depending on the X-inactivation; (2) large deletions can be missed by routine genetic analysis; and (3) only quantification of the PDHA1 gene content revealed the mutation in our patient. We recommend to revisit patients who are clinically suspicious for a mitochondrial disorder especially for hidden PDHA1 mutations, such as large deletions.
Subject(s)
Chromosome Deletion , Chromosomes, Human, X , Protein Serine-Threonine Kinases/genetics , Pyruvate Dehydrogenase (Lipoamide)/genetics , Pyruvate Dehydrogenase Complex Deficiency Disease/genetics , Spasms, Infantile/genetics , Child, Preschool , Female , Humans , InfantABSTRACT
BACKGROUND: Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups. METHODS: We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity. FINDINGS: 76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8-59·0, IQR 9-23) and a mean weight of 9·1 kg (range 4·0-15·0, IQR 7·4-10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9-19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings. INTERPRETATION: This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored. FUNDING: None. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.
Subject(s)
Body Weight/physiology , Genetic Therapy , Muscular Atrophy, Spinal/drug therapy , Oligonucleotides , Age Factors , Austria , Child, Preschool , Female , Germany , Humans , Infant , Male , Oligonucleotides/adverse effects , Oligonucleotides/therapeutic use , Prospective Studies , Surveys and QuestionnairesABSTRACT
Respiratory chain enzymes consist of multiple subunits encoded either by the mitochondrial or by the nuclear genome. Recently the first X-chromosomal mutations in complex I deficient males have been described. Heterozygous female carriers did not seem to be affected. Here, we describe a girl initially presenting with mild muscular hypotonia, a moderate lactic acidosis and an increased beta-hydroxybutyrate/acetoacetate ratio. Biochemical investigations of a muscle biopsy revealed a deficiency in the amount and activity of complex I. Mutation screening of all structural subunits of complex I identified a heterozygous mutation c.94G>C, p.Gly32Arg in the X-chromosomal NDUFA1 gene. Analysis of the cDNA showed that 72% of the expressed mRNA was mutated in the muscle biopsy sample. Investigation of the X-inactivation pattern demonstrated that 74% of the paternally inherited allele was active in the muscle. This is the first report of an X-chromosomally inherited respiratory chain defect in a heterozygous female.
Subject(s)
Electron Transport Complex I/deficiency , Genes, X-Linked , Genetic Diseases, X-Linked/genetics , Heterozygote , Mutation , NADH Dehydrogenase/genetics , Electron Transport Complex I/genetics , Female , Humans , Infant , RNA, Messenger/metabolismABSTRACT
Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.
Subject(s)
Carbohydrate Metabolism, Inborn Errors , Glucose Transporter Type 1/deficiency , Glucose Transporter Type 1/genetics , Adolescent , Adult , Age of Onset , Carbohydrate Metabolism, Inborn Errors/diagnosis , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/therapy , Child , Child, Preschool , Diet, Ketogenic , Dyskinesias/diagnosis , Dyskinesias/genetics , Dyskinesias/therapy , Epilepsy/diagnosis , Epilepsy/genetics , Epilepsy/therapy , Female , Humans , Infant , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/therapy , Male , Mutation , Phenotype , Retrospective Studies , Syndrome , Young AdultABSTRACT
OBJECTIVE: To further delineate the clinical and genetic spectrum of epileptic and neurodevelopmental conditions associated with variants in STX1B. METHODS: We screened our diagnostic in-house database (comprising >20,000 exome sequencing datasets) for pathogenic and likely pathogenic variants inSTX1B. The detected cases were phenotyped in detail, and the findings were compared to previously published case reports. RESULTS: We identified four unrelated individuals with pathogenic or likely pathogenic variants in STX1B (one missense and three loss-of-function variants). All patients displayed epileptic phenotypes, including epileptiform discharges on electroencephalography (without apparent seizures), developmental and epileptic encephalopathy and focal epilepsy. Three of the four patients had developmental delay. Febrile seizures occurred in two individuals. One patient with focal epilepsy underwent epilepsy surgery without lasting improvement. The neuropathological workup of brain tissue revealed a mild malformation of cortical development without alterations of cortical lamination or dysplastic neurons. CONCLUSIONS: Our findings confirm the wide clinical range ofSTX1B-related epileptic conditions and highlight the necessity of genetic testing prior to epilepsy surgery in cases with monogenic epilepsy. The identification of loss-of-function variants in very differently affected individuals suggests that no clear genotype-phenotype correlation can be established.
Subject(s)
Epilepsy, Generalized , Epilepsy , Electroencephalography , Epilepsy/genetics , Epilepsy, Generalized/genetics , Humans , Phenotype , Seizures , Syntaxin 1ABSTRACT
AIM: Complete or subtotal absence of one cerebellar hemisphere is exceptional; only single cases have been described. We aimed to assess the long-term outcome in children with severe unilateral cerebellar hypoplasia (UCH). METHOD: As part of a retrospective study we describe neuroimaging features, clinical findings, and cognitive outcomes of seven children with UCH (five males, two females; age at first magnetic resonance imaging [MRI]: median 1y 3mo, range 9d-8y 10mo; age at latest follow-up: median 6y 6mo, range 2y 3mo-14y 11mo). RESULTS: One child had abnormalities on prenatal MRI at 21 weeks' gestation. The left cerebellar hemisphere was affected in five children, and the right hemisphere in two children. The vermis was involved in five children. The volume of the posterior fossa was variable. At the latest follow-up, neurological findings included truncal ataxia and muscular hypotonia in five children, limb ataxia in three patients, and head nodding in two patients. Three children had learning disability*, five had speech and language disorders, and one had a severe behavioural disorder. INTERPRETATION: Severe UCH is a residual change after a disruptive prenatal cerebellar insult, most likely haemorrhagic. The outcome is variable, ranging from almost normal development to marked developmental impairment. Ataxia is a frequent but not a leading sign. It seems that involvement of the cerebellar vermis is often, but not consistently, associated with a poorer cognitive outcome, whereas an intact vermis is associated with normal outcome and no truncal ataxia.
Subject(s)
Cerebellar Diseases/pathology , Cerebellum/abnormalities , Functional Laterality/physiology , Ataxia/epidemiology , Ataxia/physiopathology , Cerebellar Diseases/epidemiology , Cerebellum/physiopathology , Child, Preschool , Cognition Disorders/diagnosis , Cognition Disorders/epidemiology , Cranial Fossa, Posterior/pathology , Female , Fetal Diseases/diagnosis , Humans , Infant , Magnetic Resonance Imaging , Male , Muscle Hypotonia/epidemiology , Muscle Hypotonia/pathology , Muscle Hypotonia/physiopathology , Muscle, Skeletal/pathology , Muscle, Skeletal/physiopathology , Pregnancy , Prenatal Diagnosis , Prevalence , Retrospective Studies , Severity of Illness IndexABSTRACT
PURPOSE: Interdisciplinary multimodal pain therapy (IMPT) programs for chronic back pain are effective and recommended. The patient-centered and biopsychosocial nature of IMPT is grounded in contemporary understanding that chronic pain states reflect heightened sensitization of the nervous system rather than an issue in the tissue. Teaching patients about pain is part of IMPT programs, though a clinical guideline is lacking. This study aims to answer the following question: Does the addition of an evidence-based pain neuroscience education (PNE) lecture for patients, into an IMPT program, produce superior results than the IMPT program itself? PATIENTS AND METHODS: A non-randomized, controlled intervention study was performed with 179 back pain patients indicated for IMPT. Intervention group (N=102) received a four-week IMPT program, which contained 4 one-hour sessions PNE. Control group (N=77) received the same IMPT without the additional PNE. Primary outcome was current pain after intervention. Pain knowledge, physical function, depression, anxiety, stress, quality of life and fear-avoidance were analyzed as secondary outcomes. Outcomes were defined as change of the parameter measured before and immediately after the four-week IMPT. For each outcome, linear regression models were used to estimate the raw and adjusted (sex, age and BMI) effect of additional PNE. RESULTS: Despite improvement in all outcomes for both groups during the treatment phase, the implemented PNE did not result in additional pain reduction (regression coefficient for PNE effect on pain level 0.34; 95% CI -6.23-6.97). Between-group differences could only be shown for pain-related knowledge in favor for the intervention group (0.78; 95% CI 0.35-1.20). CONCLUSION: The additional PNE lecture did not lead to pain reduction beyond the usual IMPT. However, the PNE did increase pain-related knowledge and, therefore, might be helpful in coping with pain after the IMPT program.
ABSTRACT
BACKGROUND: TTC19 deficiency is a progressive neurodegenerative disease associated with isolated mitochondrial respiratory chain (MRC) complex III deficiency and loss-of-function mutations in the TT19 gene in the few patients reported so far. METHODS: We performed exome sequencing and selective mutational analysis of TTC19, respectively, in patients from three unrelated families presenting with initially unspecific clinical signs of muscular hypotonia and global developmental delay followed by regression, ataxia, loss of speech, and rapid neurological deterioration. One patient showed severe lactic acidosis at the neonatal age and during intercurrent illness. RESULTS: We identified homozygous mutations in all three index cases, in two families novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro). The younger sister of the severely affected patient 3 showed only mild delay of motor skills and muscular hypotonia so far but is also homozygous for the same mutation. Notably, one patient revealed normal activities of MRC complex III in two independent muscle biopsies. Neuroimaging of the severely affected patients demonstrated lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of hypertrophic olivary nuclei degeneration. Reviewing the literature revealed striking similarities regarding neuroimaging and clinical course in pediatric patients with TTC19 deficiency: patterns consistent with Leigh or Leigh-like syndrome were found in almost all, hypertrophic olivary nucleus degeneration in all patients reported so far. The clinical course in pediatric patients is characterized by an initially unspecific developmental delay, followed by regression, progressive signs and symptoms of cerebellar, basal ganglia and brainstem affection, especially loss of speech and ataxia. Subsequently, neurological deterioration leading to a vegetative state occurs. CONCLUSIONS: Our findings add to the phenotypic, genetic, and biochemical spectrum of TTC19 deficiency. However, TTC19 deficient patients do show characteristic clinical and neuroimaging features, which may facilitate diagnosis of this yet rare disorder. Normal MRC complex III activity does not exclude the diagnosis.
Subject(s)
Membrane Proteins/deficiency , Membrane Proteins/genetics , Mitochondrial Proteins/deficiency , Mitochondrial Proteins/genetics , Neurodegenerative Diseases/genetics , Adolescent , Amino Acid Sequence , Child , Child, Preschool , Cloning, Molecular , Female , Gene Expression Regulation , Humans , Infant , Infant, Newborn , Male , Membrane Proteins/metabolism , Mitochondrial Proteins/metabolism , MutationSubject(s)
Amelogenesis Imperfecta/genetics , Dementia/genetics , Epilepsy/genetics , Gene Deletion , Amelogenesis Imperfecta/diagnostic imaging , Amelogenesis Imperfecta/pathology , Amelogenesis Imperfecta/physiopathology , Brain/diagnostic imaging , Child , Dementia/diagnostic imaging , Dementia/pathology , Dementia/physiopathology , Dental Enamel/pathology , Developmental Disabilities/diagnostic imaging , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Epilepsy/diagnostic imaging , Epilepsy/pathology , Epilepsy/physiopathology , Humans , Male , Seizures/diagnostic imaging , Seizures/genetics , Seizures/physiopathologyABSTRACT
Considerable non-allelic heterogeneity for autosomal recessively inherited Charcot-Marie-Tooth (ARCMT) disease has challenged molecular testing and often requires a large amount of work in terms of DNA sequencing and data interpretation or remains unpractical. This study tested the value of SNP array-based whole-genome homozygosity mapping as a first step in the molecular genetic diagnosis of sporadic or ARCMT in patients from inbred families or outbred populations with the ancestors originating from the same geographic area. Using 10 K 2.0 and 250 K Nsp Affymetrix SNP arrays, 15 (63%) of 24 CMT patients received an accurate genetic diagnosis. We used our Java-based script eHoPASA CMT-easy Homozygosity Profiling of SNP arrays for CMT patients to display the location of homozygous regions and their extent of marker count and base-pairs throughout the whole genome. CMT4C was the most common genetic subtype with mutations detected in SH3TC2, one (p.E632Kfs13X) appearing to be a novel founder mutation. A sporadic patient with severe CMT was homozygous for the c.250G > C (p.G84R) HSPB1 mutation which has previously been reported to cause autosomal dominant dHMN. Two distantly related CMT1 patients with early disease onset were found to carry a novel homozygous mutation in MFN2 (p.N131S). We conclude that SNP array-based homozygosity mapping is a fast, powerful, and economic tool to guide molecular genetic testing in ARCMT and in selected sporadic CMT patients.