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Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal-onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult. We present neuroimaging and electroencephalography together with clinical and biochemical data. Incidence of MSUD (1972-2018) was 1 in 147 975. Overall good clinical outcomes were achieved with 15/18 patients alive and with essentially normal functioning (with only the lowest performing cluster lying beyond a single SD on their full scale intelligence quotient). Molecular genetic analysis revealed genotypes hitherto not reported, including a possible digenic inheritance state for the BCKDHA and DBT genes in one family. Treatment has been based on early implementation of emergency treatment, diet, close monitoring, and even dialysis in the setting of acute metabolic decompensation. A plasma leucine ≥400 µmol/L (outside therapeutic range) was more frequently observed in infancy or during adolescence, possibly due to infections, hormonal changes, or noncompliance. Children require careful management during metabolic decompensations in early childhood, and this represented a key risk period in our cohort. A high level of metabolic control can be achieved through diet with early implementation of a "sick day" regime and, in some cases, dialysis as a rescue therapy. The Irish cohort, despite largely classical phenotypes, achieved good outcomes in the NBS era, underlining the importance of early diagnosis and skilled multidisciplinary team management.
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Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/genética , Adolescente , Niño , Preescolar , Dieta con Restricción de Proteínas , Pruebas con Sangre Seca , Diagnóstico Precoz , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Irlanda , Leucina/sangre , Masculino , Tamizaje Neonatal/métodos , Fenotipo , Estudios RetrospectivosRESUMEN
Background Irish Travellers are an endogamous, nomadic, ethnic minority population mostly resident on the island of Ireland with smaller populations in Europe and the USA. High levels of consanguinity result in many rare autosomal recessive disorders. Due to founder effects and endogamy, most recessive disorders are caused by specific homozygous mutations unique to this population. Key clinicians and scientists with experience in managing rare disorders seen in this population have developed a de facto advisory service on differential diagnoses to consider when faced with specific clinical scenarios. Objective(s) To catalogue all known inherited disorders found in the Irish Traveller population. Methods We performed detailed literature and database searches to identify relevant publications and the disease mutations of known genetic disorders found in Irish Travellers. Results We identified 104 genetic disorders: 90 inherited in an autosomal recessive manner; 13 autosomal dominant and one a recurring chromosomal duplication. Conclusion We have collated our experience of inherited disorders found in the Irish Traveller population to make it publically available through this publication to facilitate a targeted genetic approach to diagnostics in this ethnic group.
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Enfermedades Genéticas Congénitas/epidemiología , Enfermedades Genéticas Congénitas/genética , Genética de Población/clasificación , Consanguinidad , Etnicidad/genética , Europa (Continente)/epidemiología , Enfermedades Genéticas Congénitas/clasificación , Humanos , Irlanda/epidemiología , Grupos Minoritarios , Mutación , Población BlancaRESUMEN
BACKGROUND: Urea cycle disorders (UCDs) still have a poor prognosis despite several therapeutic advancements. As liver transplantation can provide a cure, liver cell therapy (LCT) might be a new therapeutic option in these patients. METHODS: Twelve patients with severe UCDs were included in this prospective clinical trial. Patients received up to six infusions of cryopreserved human heterologous liver cells via a surgically placed catheter in the portal vein. Portal vein pressure, portal vein flow, and vital signs were monitored continuously. Calcineurin inhibitors and steroids were used for immunosuppression. In four patients, ureagenesis was determined with stable isotopes. Number and severity of hyperammonemic events and side effects of immunosuppression were analyzed during an observation period of up to 2 years. RESULTS: No study-related mortality was observed. The application catheter dislocated in two children. No significant side effects of catheter application or cell infusion were noted in the other ten patients. The overall incidence of infections did not differ significantly from a historical control group, and no specific side effects of immunosuppression were found. Seven patients were treated per protocol and could be analyzed for efficacy. Severe metabolic crises could be prevented in all of these patients, moderate crises in four of seven. Ureagenesis increased after cell infusion in all patients investigated. CONCLUSIONS: We found a favorable safety profile with respect to catheter placement, intraportal liver cell infusion, and immunosuppression. More than half of the children treated per protocol experienced metabolic stabilization and could be safely bridged to liver transplantation.
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Amoníaco/sangre , Trasplante de Células/métodos , Hiperamonemia/cirugía , Trasplante de Hígado/métodos , Hígado/citología , Trastornos Innatos del Ciclo de la Urea/cirugía , Urea/sangre , Biomarcadores/sangre , Trasplante de Células/efectos adversos , Europa (Continente) , Femenino , Humanos , Hiperamonemia/sangre , Hiperamonemia/diagnóstico , Hiperamonemia/etiología , Lactante , Recién Nacido , Trasplante de Hígado/efectos adversos , Masculino , Estudios Prospectivos , Factores de Tiempo , Resultado del Tratamiento , Trastornos Innatos del Ciclo de la Urea/sangre , Trastornos Innatos del Ciclo de la Urea/complicaciones , Trastornos Innatos del Ciclo de la Urea/diagnósticoRESUMEN
BACKGROUND: Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects. METHODS: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors. RESULTS: We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2â years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6â years vs 8â months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement. CONCLUSIONS: The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.
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More than 650 inherited metabolic diseases may present with epilepsy or seizures. These diseases are often multisystem, life-long and induce complex needs of patients and families. Multidisciplinary care involves all stages of disease management: diagnostics, specific or symptomatic, acute and chronic treatments, and integrated care that takes into account not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers. Care coordination is indispensable to ensure smooth transitions of care across life and disease stages, including management of emergencies, transition from pediatric to adult services and palliative care. Care pathways are highly diverse and have to find the right balance between highly specialized and locally provided services. While multidisciplinary teams consist of many professionals, a named supervising physician in a highly specialized healthcare setting and a care coordinator are highly important. As the greatest burden of care always falls onto the shoulders of patients and/or families, patient empowerment should be a part of every care pathway and include provision of required information, involvement into common decision-making, patient's and family's education, support for self-management, liaison with peer support groups and emotional/ psychological support. Due to the rarity and complexity of these diseases, sufficient expertise may not be available in a national healthcare system and cross-border services (virtual or physical) in the recently developed European Reference Networks should be ensured through the proper organization of referral systems in each EU and EEA country. Finally, digital technologies are particularly important in the provision of services for patients with rare diseases and can significantly increase the availability of highly specialized services and expertise.
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Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder that can lead to encephalopathic crises and severe dystonic movement disorders. Adherence to strict dietary restriction, in particular a diet low in lysine, carnitine supplementation and emergency treatment in pre-symptomatic patients diagnosed by high-risk screen (HRS) or newborn screen (NBS) leads to a favourable outcome. We present biochemical and clinical characteristics and long-term outcome data of 34 Irish patients with GA1 aged 1-40 years. Sixteen patients were diagnosed clinically, and 17 patients by HRS, prior to introduction of NBS for GA1 in the Republic of Ireland in 2018. One patient was diagnosed by NBS. Clinical diagnosis was at a median of 1 year (range 1 month to 8 years) and by HRS was at a median of 4 days (range 3 days to 11 years). 14/18 (77.8%) diagnosed by HRS or NBS had neither clinical manifestations nor radiological features of GA1, or had radiological features only, compared to 0/16 (0%) diagnosed clinically (p < 0.001). Patients diagnosed clinically who survived to school-age were more likely to have significant cerebral palsy and dystonia (7/11; 63.6% vs. 0/13; 0%, p < 0.001). They were less likely to be in mainstream school versus the HRS group (5/10; 50% vs. 12/13; 92.3%; p = 0.012). Clinical events occurring after 6 years of age were unusual, but included spastic diplegia, thalamic haemorrhage, Chiari malformation, pituitary hormone deficiency and epilepsy. The exact aetiology of these events is unclear.
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Mucolipidosis type II (ML II) is an autosomal recessive lysosomal targeting disorder that may present with features of hyperparathyroidism. The aim of this study was to describe in detail the clinical cases of ML II presenting to a tertiary referral centre with biochemical and/or radiological features of hyperparathyroidism. There were twenty-three children diagnosed with ML II in the Republic of Ireland from July 1998 to July 2021 inclusive (a 23-year period). The approximate incidence of ML II in the Republic of Ireland is, therefore, 1 per 64,000 live births. Medical records were available and were reviewed for 21 of the 23 children. Five of these had been identified as having biochemical and/or radiological features of hyperparathyroidism. Of these five, three children were born to Irish Traveller parents and two to non-Traveller Irish parents. All five children had radiological features of hyperparathyroidism (on skeletal survey), with evidence of antenatal fractures in three cases and an acute fracture in one. Four children had biochemical features of secondary hyperparathyroidism. Three children received treatment with high dose Vitamin D supplements and two who had antenatal/acute fractures were managed with minimal handling. We observed resolution of secondary hyperparathyroidism in all cases irrespective of treatment. Four of five children with ML II and hyperparathyroidism died as a result of cardiorespiratory failure at ages ranging from 10 months to 7 years. Biochemical and/or radiological evidence of hyperparathyroidism is commonly identified at presentation of ML II. Further studies are needed to establish the pathophysiology and optimal management of hyperparathyroidism in this cohort. Recognition of this association may improve diagnostic accuracy and management, facilitate family counseling and is also important for natural history data.
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Elevated levels of plasma homocysteine (Hcy) are an independent risk factor for cardiovascular disease and thrombosis. The molecular basis for this phenomenon is not known but may relate to modification of cell surface thiols. The platelet specific integrin α(IIb)ß3 is a cysteine-rich cell adhesion molecule that plays a critical role in platelet aggregation and adhesion in haemostasis and thrombosis. In this study, we looked for evidence of a homocysteine-induced modification of α(IIb)ß3 using a fluorescently labeled PAC-1 antibody that recognizes the activated conformation of the integrin on the platelet surface. We show that exogenous Hcy (10-100 µM) and homocysteine thiolactone (HcyTL) (10-100 µM) increased PAC-1 binding to platelets in a concentration dependent manner in vitro. In parallel, we show subjects with clinical hyperhomocysteinemia exhibit a greater degree of activation of α(IIb)ß3 compared to age-matched controls. These findings demonstrate that circulating Hcy can modulate the activation state of the platelet integrin α(IIb)ß3, a key player in platelet aggregation and thrombosis.
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Homocisteína/metabolismo , Hiperhomocisteinemia/metabolismo , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/metabolismo , Trombosis/metabolismo , Anticuerpos/metabolismo , Sitios de Unión de Anticuerpos/efectos de los fármacos , Plaquetas/metabolismo , Estudios de Casos y Controles , Femenino , Homocisteína/análogos & derivados , Homocisteína/farmacología , Humanos , Hiperhomocisteinemia/complicaciones , Hiperhomocisteinemia/fisiopatología , Integrinas/metabolismo , Masculino , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Factores de Riesgo , Compuestos de Sulfhidrilo/metabolismo , Trombosis/etiología , Trombosis/fisiopatologíaRESUMEN
Many patients with inborn errors of metabolism, due to early diagnosis and improved management, are living longer with less disease burden. Several are now having families of their own. This poses challenges both for the metabolic control of the mother and potential secondary effects on the fetus, as well as the risk of inheriting the inborn error. Classical homocystinuria (HCU, OMIM 236200) is a rare multisystem condition with intellectual, skeletal, ocular, and thromboembolic complications. Ireland has included HCU in the National Newborn Bloodspot Screening Program since 1971. The European network and registry for homocystinurias and methylation defects (E-HOD) guidelines outline the requirements for management and monitoring of this condition and associated complications. Pregnancy alone has many potential complications. When combined with an underlying condition such as HCU, which is prothrombotic and requires a highly medicalized diet, there are significantly increased risks to both mother and baby. Colleagues previously published an Irish case of maternal HCU with successful pregnancy outcome. We add five pregnancies to two women with classical HCU to the literature. We use these to highlight the importance of careful metabolic control and managing the predictable HCU associated risks during pregnancy and the postpartum period. Our cases demonstrate the potential for healthy pregnancies in HCU and that this is best achieved with a motivated clinical team and good patient engagement. Only small numbers of pregnancies in HCU have been reported and we are still learning best practice, but proactive management is essential, as in any inborn error of metabolism.
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OBJECTIVES: To determine the long-term outcome of dietary intervention in siblings from 14 Irish families with classical galactosemia (McKusick 230400), an autosomal recessive disorder of carbohydrate metabolism and galactose-1-phosphate uridyltransferase (GALT) deficiency. STUDY DESIGN: Outcomes in siblings on dietary galactose restriction were studied to evaluate whether birth order (ie, time of commencement of diet) and compliance with lactose-restricted diet (galactose intake > or < 20 mg /day), assessed by dietary recall and biochemical monitoring of galactose-1-phosphate [Gal-1-P] and galactitol values, affected outcomes. The outcome variables assessed were IQ, speech, and language assessment scores, neurologic examination results, and magnetic resonance imaging (MRI) of the brain. RESULTS: There was a high incidence of complications in the overall group, particularly speech and language delay (77%) and low IQ (71%). There was no significant difference in outcome between earlier-treated and later-treated siblings or any correlation with mean Gal-1-P or galactitol values. In most cases, cerebral white matter disease was evident on MRI scanning, with evidence of progressive cerebellar degeneration seen in 2 highly compliant families. CONCLUSION: The subjects with a higher galactose intake did not exhibit an increased incidence of complications; conversely, those who were very compliant with dietary restrictions did not have more favorable outcomes.
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Encéfalo/patología , Galactosemias/complicaciones , Galactosemias/dietoterapia , Pruebas de Inteligencia , Trastornos del Lenguaje/etiología , Hermanos , Adolescente , Adulto , Orden de Nacimiento , Niño , Preescolar , Registros de Dieta , Femenino , Galactitol/orina , Galactosa/administración & dosificación , Galactosemias/genética , Galactosafosfatos/sangre , Humanos , Lactante , Irlanda , Lactosa/administración & dosificación , Espectroscopía de Resonancia Magnética , Masculino , Examen Neurológico , Cooperación del Paciente , Estudios Retrospectivos , Adulto JovenRESUMEN
Guanidinoacetate methyltransferase (GAMT) deficiency is a disorder of creatine biosynthesis, characterized by early-onset learning disability and epilepsy in most affected children. Severe expressive language delay is a constant feature even in the mildest clinical phenotypes.We report the clinical, biochemical, imaging, and treatment data of two female siblings (18y and 13y) with an unusual phenotype of GAMT deficiency. The oldest sibling had subacute onset of a movement disorder at age 17 years, later than has been previously reported. The younger sibling had better language skills than previously described in this disorder. After treatment with creatine, arginine restriction and ornithine-supplemented diet, seizure severity and movement disorder were reduced but cognition did not improve. This report confirms that GAMT deficiency, a heterogeneous, potentially treatable disorder, detected by increased levels of guanidinoacetate in body fluids (e.g. plasma or urine) or by an abnormal creatine peak on magnetic resonance spectroscopy, should be considered in patients of any age with unexplained, apparently static learning disability and epilepsy.
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Encéfalo/patología , Guanidinoacetato N-Metiltransferasa/deficiencia , Trastornos del Desarrollo del Lenguaje/dietoterapia , Trastornos del Desarrollo del Lenguaje/enzimología , Discapacidades para el Aprendizaje/enzimología , Trastornos del Movimiento/dietoterapia , Trastornos del Movimiento/enzimología , Administración Oral , Adolescente , Edad de Inicio , Biomarcadores/sangre , Biomarcadores/orina , Creatina/uso terapéutico , Creatinina/sangre , Creatinina/orina , Femenino , Guanidinoacetato N-Metiltransferasa/sangre , Guanidinoacetato N-Metiltransferasa/orina , Humanos , Trastornos del Desarrollo del Lenguaje/patología , Discapacidades para el Aprendizaje/dietoterapia , Discapacidades para el Aprendizaje/patología , Imagen por Resonancia Magnética , Trastornos del Movimiento/patología , Ornitina/uso terapéutico , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Gemelos DicigóticosRESUMEN
BACKGROUND: Classical homocystinuria is an autosomal recessive disorder caused by profound cystathionine ß-synthase deficiency. Its biochemical hallmarks are high concentrations of plasma homocyst(e)ine and methionine. Clinical manifestations include lens dislocation, developmental delay, skeletal anomalies, or thromboembolism. Limited literature exists outlining the risk of encephalopathy associated with hypermethioninemia presenting in children with classical homocystinuria. AIM: To assess the quality of metabolic control and plasma methionine concentrations in infancy in a cohort of 36 patients with classical homocystinuria in the Republic of Ireland. METHODS: Review of biochemical and clinical data including neuroradiological results that are available for the first year of life in our patients diagnosed on newborn screening was performed with appropriate consent and ethical approval. RESULTS AND DISCUSSION: Median total homocyst(e)ine and methionine plasma concentrations were 78 and 55 µmol/L, respectively. Methionine concentrations were significantly higher in neonates as opposed to older children. The highest methionine level identified was 1329 µmol/L in a child who presented clinically with encephalopathy. Elevated homocyst(e)ine and methionine levels are associated with significant morbidities. Therefore, prevention of complications requires prompt recognition and treatment. Chronic and acute complications may be encountered in patients with classical homocystinuria and plasma methionine concentrations pose an additional risk factor.
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The Metabolic Dietetic Team in the National Centre for Inherited Metabolic Disorders (NCIMD) in Ireland deals with approximately 120 weekly phenylalanine (Phe) levels for both adults and children. A review of 500 Phe levels highlighted that 52% of the results were within the target range. Collaboration between information and communication technologies (ICT) departments, metabolic laboratory, and metabolic dietitians enabled the development of the PKU texting system. Following a successful pilot study, the system was then offered to all PKU patients aged over 2 years. The Phe is analysed and authorised on the laboratory system. The demographics are matched with the patient mobile phone number. Text messages are then validated and sent by the dietitian via a web portal using the Defero SMS texting service. Approximately 290 patients/families currently use the texting system. In order to assess the effectiveness of this quality improvement initiative, a patient survey was carried out in 2017. This showed 87% rated the system as either very good or excellent. 94% agreed it was time saving. 84% felt there was no influence on dietary compliance. Analysis of financial implications on dietetic time over 21 months revealed savings of 3,275 and 580 hours of dietetic time. There is no evidence, two years after implementation, that the system has had an effect on either the Phe levels in terms of recommended range or frequency of sampling.
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A low methionine diet is the mainstay of treatment for pyridoxine nonresponsive homocystinuria (HCU). There are various guidelines for recommended protein intakes for HCU and clinical practice varies. Poor growth has been associated with low cystine levels. This retrospective review of 48 Irish pyridoxine nonresponsive HCU patients assessed weight, height, body mass index (BMI), protein intake, and metabolic control up to 18 years at nine set time points. Patients diagnosed through newborn screening (NBS) were compared to late diagnosed (LD) patients. At 18 years the LD group (n = 12, mean age at diagnosis 5.09 years) were heavier (estimated effect +4.97 Kg, P = 0.0058) and taller (estimated effect +7.97 cm P = 0.0204) than the NBS group (n = 36). There was no difference in growth rate between the groups after 10 years of age. The HCU population were heavier and taller than the general population by one standard deviation with no difference in BMI. There was no association between intermittently low cystine levels and height. Three protein intake guidelines were compared; there was no difference in adult height between those who met the lowest of the guidelines (Genetic Metabolic Dietitians International) and those with a higher protein intake.
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BACKGROUND: Leukoencephalopathy with temporal lobe cysts may be associated with monogenetic conditions such as Aicardi-Goutières syndrome or RNASET2 mutations and with congenital infections such as cytomegalovirus. In view of the fact that congenital cytomegalovirus is difficult to confirm outside the neonatal period, excluding a Mendelian disorder is extremely relevant, changing family planning and medical management in affected families. We performed diagnostic testing in individuals with leukoencephalopathy with temporal lobe cysts without a definitive diagnosis of congenital cytomegalovirus infection. METHODS: We reviewed a large-scale biorepository of patients with unsolved leukodystrophies and identified two individuals with required for meiotic nuclear division 1 (RMND1) mutations and similar magnetic resonance imaging (MRI) features, including temporal lobe cysts. Ten additional subjects with confirmed RMND1 mutations were identified as part of a separate disease specific cohort. Brain MRIs from all 12 individuals were reviewed for common neuroradiological features. RESULTS: MRI features in RMND1 mutations included temporal lobe swelling, with rarefaction and cystic evolution, enlarged tips of the temporal lobes, and multifocal subcortical white matter changes with confluent periatrial T2 signal hyperintensity. A combination of these features was present in ten of the 12 individuals reviewed. CONCLUSIONS: Despite the small number of reported individuals with RMND1 mutations, a clinically recognizable phenotype of leukoencephalopathy with temporal lobe swelling, rarefaction, and cystic changes has emerged in a subset of individuals. Careful clinical phenotyping, including for lactic acidosis, deafness, and severe muscle involvement seen in RMND1 mutation positive individuals, and MRI pattern recognition will be important in differentiating these patients from children with congenital infections like cytomegalovirus.
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Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Infecciones por Citomegalovirus/congénito , Sordera/genética , Leucoencefalopatías/genética , Neoplasias Encefálicas/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Quistes/diagnóstico por imagen , Infecciones por Citomegalovirus/diagnóstico por imagen , Infecciones por Citomegalovirus/genética , Sordera/diagnóstico por imagen , Diagnóstico Diferencial , Humanos , Lactante , Leucoencefalopatías/diagnóstico por imagen , Mutación , Fenotipo , Lóbulo Temporal/diagnóstico por imagenRESUMEN
We report a female child from an Irish Traveller family presenting with severe intellectual disability, dysmorphic features, renal anomalies, dental caries and cyclical vomiting. Current health issues include global developmental delay, mild concentric left ventricular hypertrophy, dental malocclusion and caries and a single duplex left kidney. The proband and her mother also have multiple epiphyseal dysplasia. Whole-exome sequencing was performed to identify the underlying genetic cause. DNA from the proband was enriched with the Agilent Sure Select v5 Exon array and sequenced on an Illumina HiSeq. Rare homozygous variants were prioritized. Whole-exome sequencing identified three linked homozygous missense variants in THOC6 (c.298T>A, p.Trp100Arg; c.700G>C, p.Val234Leu; c.824G>A, p.Gly275Asp) as the likely cause of this child's intellectual disability syndrome, resulting in a molecular diagnosis of Beaulieu-Boycott-Innes syndrome (BBIS). This is the first report of BBIS in Europe. BBIS has been reported previously in two Hutterite families and one Saudi family. A review of all patients to date shows a relatively homogenous phenotype. Core clinical features include low birth weight with subsequent growth failure, short stature, intellectual disability with language delay, characteristic facies, renal anomalies and dental malocclusion with caries. Some patients also have cardiac defects. All patients show characteristic dysmorphic facial features including a tall forehead with high anterior hairline and deep-set eyes with upslanting palpebral fissures. The coexistence of intellectual disability together with these characteristic facies should provide a diagnostic clue for BBIS during patient evaluation.
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Facies , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Fenotipo , Alelos , Niño , Exoma , Femenino , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linaje , SíndromeRESUMEN
A fatigued 8-year-old boy was found to have sideroblastic anaemia (haemoglobin 7.8 g/dL) which over time became transfusion dependent. Subtle neurological dysfunction, initially manifesting as mild spastic diplegia, was slowly progressive and ultimately led to wheelchair dependence. Elevated plasma lactate and urinary 3-methylglutaconate led to a muscle biopsy which confirmed partial complex IV deficiency. PCR in leucocytes and muscle was negative for mitochondrial DNA (mtDNA) deletions. Faltering growth prompted an insulin tolerance test which confirmed growth hormone sufficiency and adrenal insufficiency. Plasma renin was elevated and adrenal androgens were low, suggesting primary adrenal insufficiency. Glucocorticoid and mineralocorticoid replacement therapy was initiated. A renal tubular Fanconi syndrome and diabetes mellitus developed subsequently. Sideroblastic anaemia and primary adrenal insufficiency, both individually and collectively, are associated with mtDNA deletion; however, absence of the same does not exclude the possibility that sideroblastic anaemia and primary adrenal insufficiency are of mitochondrial origin.