ABSTRACT
BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism caused by a deficiency of the enzyme phenylalanine hydroxylase. If untreated, the complications of PKU lead to significant neucognitive and neuropsychiatric impairments, placing a burden on both the individual's quality of life and on the healthcare system. We conducted a systematic literature review to characterize the impact of PKU on affected individuals and on healthcare resources in Latin American (LATAM) countries. METHODS: Searches of the global medical literature as well as regional and local medical literature up to September 2021. Observational studies on patients with PKU from any LATAM country. Pairs of reviewers independently screened eligible articles, extracted data from included studies, and assessed their risk of bias. RESULTS: 79 unique studies (47 cross-sectional studies, 18 case series, 12 case reports, and two cohort studies) with a total of 4090 patients were eligible. Of these studies, 20 had data available evaluating early-diagnosed PKU patients for meta-analysis of burden outcomes. Intellectual disability in the pooled studies was 18% [95% Confidence Interval (CI) 0.04-0.38; I2 = 83.7%, p = 0.0133; two studies; n = 114]. Motor delay was 15% [95% CI 0.04-0.30; I2 = 74.5%, p = 0.0083; four studies; n = 132]. Speech deficit was 35% [95% CI 0.08-0.68; I2 = 93.9%, p < 0.0001; five studies; n = 162]. CONCLUSIONS: There is currently evidence of high clinical burden in PKU patients in LATAM countries. Recognition that there are many unmet neuropsychological needs and socioeconomic challenges faced in the LATAM countries is the first step in planning cost-effective interventions.
Subject(s)
Phenylalanine Hydroxylase , Phenylketonurias , Cross-Sectional Studies , Humans , Latin America/epidemiology , Phenylketonurias/complications , Quality of LifeABSTRACT
Mucopolysaccharidosis type II (MPSII) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase (IDS). The human IDS gene is located in chromosome Xq28. This is the first report of genotype and phenotype characterization of 49 Hunter patients from 40 families of Argentina. Thirty different alleles have been identified, and 57% were novel. The frequency of de novo mutations was 10%. Overall, the percentage of private mutations in our series was 75%.
ABSTRACT
In this work, we review the clinical and genetic data in 14 Latin American propionic acidemia (PA) and 15 methylmalonic aciduria (MMAuria) patients. In the PA patients, we have identified four different changes in the PCCA gene, including one novel one (c.414+5G>A) affecting the splicing process. The PCCB mutational spectrum included two prevalent changes accounting for close to 60% of the mutant alleles studied and one novel change (c.494G>C) which by functional analysis is clearly pathogenic. We have also identified the deep intronic change c.654+462A>G, and the results of the antisense treatment in the patient's cell line confirmed the functional recovery of PCC activity. All PA patients bearing out-of-frame mutations presented the disease earlier while patients bearing in hemizygous fashion p.E168K and p.R165W presented the disease later. Regarding the MMAuria patients, we have found three novel mutations in the MUT gene (c.1068G>A, c.1587_1594del8 and c.593delA) and one in the MMAB gene (c.349-1 G>C). Two patients with MMAuria with homocystinuria cblC type are carriers of the frequent c.271dupA mutation. All mut(0), cblB and cblC patients presented the symptoms early and in general had more neurological complications, while cblA and mut(-) patients exhibited a late-onset presentation, and in general the long-term outcome was better. The results presented in this work emphasize the importance of the genetic analysis of the patients not only for diagnostic purposes but also to research into novel therapies based on the genotype.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Methylmalonic Acid/urine , Methylmalonyl-CoA Decarboxylase/genetics , Methylmalonyl-CoA Mutase/genetics , Mutation , Propionic Acidemia/genetics , Adolescent , Adult , Age of Onset , Amino Acid Metabolism, Inborn Errors/enzymology , Amino Acid Metabolism, Inborn Errors/mortality , Amino Acid Metabolism, Inborn Errors/therapy , Amino Acid Metabolism, Inborn Errors/urine , Cell Line , Child , Child, Preschool , DNA Mutational Analysis , Genotype , Humans , Infant , Infant, Newborn , Introns , Latin America , Methylmalonyl-CoA Decarboxylase/metabolism , Methylmalonyl-CoA Mutase/metabolism , Phenotype , Propionic Acidemia/enzymology , Propionic Acidemia/mortality , Propionic Acidemia/therapy , Time Factors , Treatment Outcome , Young AdultSubject(s)
Carnitine/analogs & derivatives , Fatty Acid Desaturases/deficiency , Lipid Metabolism, Inborn Errors/diet therapy , Lipid Metabolism, Inborn Errors/diagnosis , Acyl-CoA Dehydrogenase , Carnitine/blood , Female , Humans , Infant , Lipid Metabolism, Inborn Errors/blood , Mass Spectrometry/methods , Monitoring, Physiologic/methodsABSTRACT
A 24-h fasting test was performed in 48 control children, in 9 hypoketotic patients with inherited defects of fatty acid oxidation and in 2 hyperketotic patients with inherited defects of ketolysis. The control group was then divided into three age groups on the basis of different adaptation to fasting. Concentrations of blood glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate, acetoacetate and carnitine were measured after 15 h, 20 h and 24 h of fasting. Significant negative correlations were found in the control group between plasma total ketone bodies (KB) and plasma glucose (P less than 0.001), plasma carnitine (P less than 0.005) and the amplitude of glycaemic response to glucagon at the end of the fast (P less than 0.01). FFA/KB ratio and the product of final fasting values of glucose and ketones were useful to differentiate between hypoketotic or hyperketotic patients and normal subjects. In children with a suspected or definite hyperketotic or hypoketotic disorder, a fasting test must only be performed in healthy patients, in good nutritional condition with non-diagnostic basal biochemical investigations. Carefully supervised fasting should be continued sufficiently to allow ketogenesis and ketolysis to become activated.
Subject(s)
Fasting/blood , Ketone Bodies/blood , 3-Hydroxybutyric Acid , Adolescent , Blood Glucose/analysis , Child , Child, Preschool , Fatty Acids, Nonesterified/blood , Female , Humans , Hydroxybutyrates/blood , Hypoglycemia/blood , Infant , Lipid Metabolism, Inborn Errors/diagnosis , MaleABSTRACT
Suspicion of hereditary disorders of the intermediary metabolism must be aroused by every neonatal disease associated with a neurological affection without an apparent cause, with ketonuria, metabolic acidosis or hypoglycaemia. These disorders can be suspected clinically by common laboratory examinations. The correct diagnosis is important, as some of these diseases respond well to early treatment. The diagnosis is of fundamental importance also in those hereditary metabolic diseases which are so far incurable (prognosis of a future pregnancy). Based on their experience with 218 neonates, the authors differentiate between five groups of these diseases. Their characteristic may be a guideline for initiation of adequate therapy and for special examinations.
Subject(s)
Metabolism, Inborn Errors , Humans , Infant, Newborn , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/therapyABSTRACT
We report the cases of 5 patients from 2 sibships with the "adult" or chronic form of GM2 gangliosidosis and 2 patients from another sibship with the juvenile form. We demonstrated hexosaminidase A deficiency in all cases but in 1 sibship the enzymatic profile was identical to that in Tay-Sachs disease, whereas in the remaining 2 families it was that of the B1 variant. There was no correlation between the clinical features and the enzymatic profile. Hexosaminidase A deficiency should be considered in unexplained progressive neurologic disorders of childhood and adolescence, including isolated dementia. EMG evidence of anterior horn cell involvement in association with neurologic or cognitive deterioration may be a diagnostic clue in the juvenile forms.
Subject(s)
Tay-Sachs Disease/enzymology , Adolescent , Biopsy , Child , Child, Preschool , Chronic Disease , Female , Fibroblasts/enzymology , Hexosaminidase A , Humans , Leukocytes/enzymology , Male , Skin/pathology , Tay-Sachs Disease/genetics , Tay-Sachs Disease/pathology , beta-N-Acetylhexosaminidases/deficiency , beta-N-Acetylhexosaminidases/metabolismABSTRACT
Every newborn with unexplained neurological deterioration, ketosis, metabolic acidosis or hypoglycaemia should be suspected of having an inherited error of intermediary metabolism. Many of these conditions can be diagnosed clinically with the aid of simple laboratory investigations. Since a substantial number of these diseases respond well to treatment but may otherwise be fatal, and in order to assure adequate prenatal diagnosis in subsequent pregnancies, a high index of suspicion and rapid diagnosis are necessary in the face of the clinical presentations described. According to three major clinical presentations observed in 218 neonates with inborn errors of intermediary metabolism (neurological distress 'intoxication' type, neurological distress 'energy-deficiency' type and hypoglycaemia with liver dysfunction) and according to the proper use of few laboratory investigations, we propose a method of diagnosis which groups these children into five categories. Initial therapy, and sophisticated investigations can be planned on the basis of this grouping.
Subject(s)
Metabolism, Inborn Errors/diagnosis , Energy Metabolism , Humans , Hypoglycemia/etiology , Infant, Newborn , Ketosis/etiology , Metabolism, Inborn Errors/classification , Metabolism, Inborn Errors/etiology , Nervous System Diseases/diagnosis , Nervous System Diseases/etiologyABSTRACT
Three children with circumscribed unilateral pial angiomatosis had both generalised and partial seizures associated with bilateral synchronous spike-wave complexes. Dramatic control of the seizures was obtained by surgical removal restricted to the angiomas and underlying cortex. There was recurrence of seizures in one patient from whom only one of two angiomatous areas was removed but not in the two patients whose excision was total. These cases indicate that secondary bilateral synchrony can occur with lesions of the posterior and external parts of one hemisphere. Surgical removal of a definable lesion, without intracranial recording, can help patients with intractable epilepsy due to unilateral pial angiomatosis, even in the presence of wide diffusion of clinical and electroencephalographic abnormalities.
Subject(s)
Angiomatosis/surgery , Electroencephalography , Epilepsies, Partial/surgery , Meningeal Neoplasms/surgery , Pia Mater/surgery , Adolescent , Angiomatosis/physiopathology , Calcinosis/surgery , Cerebral Cortex/physiopathology , Cerebral Cortex/surgery , Child , Child, Preschool , Epilepsies, Partial/physiopathology , Evoked Potentials , Female , Humans , Meningeal Neoplasms/physiopathology , Postoperative Complications/physiopathologyABSTRACT
From the description of 2 unrelated patients with succinyl-CoA transferase (3-OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of 'fasting ketoacidosis' or 'idiopathic ketotic hypoglycemia', mainly when severe metabolic acidosis is present.
Subject(s)
Coenzyme A-Transferases , Ketones/blood , Metabolism, Inborn Errors/blood , Sulfurtransferases/deficiency , Acetoacetates/blood , Acetyl-CoA C-Acetyltransferase/deficiency , Female , Humans , Hydroxybutyrates/blood , Male , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/geneticsSubject(s)
Ataxia Telangiectasia/pathology , Myelin Sheath/ultrastructure , Spinal Nerves/pathology , Sural Nerve/pathology , Atrophy , Brain/pathology , Child , Humans , MaleABSTRACT
La neuropatía periférica correspondiente al síndrome de ataxia telangiectasia es poco conocida. Se presenta un caso en un niño de 9 años de edad, con antecedentes familiares de padre, madre y hermanos con telangiectasias conjuntivales. A la edad de tres años comienza con signos centrales, caídas frecuentes, babeo y temblores en miembros superiores, estrabismo convergente de ojo derecho y nistagmus lateral y vertical. Al examen neurológico se encuentra hipotrofia muscular en ambas piernas, con caída de ambos antepiés, arreflexia en miembros inferiores y sensibilidad superficial y profunda conservada. Se detectó atrofia cerebelosa por tomografía computada y la velocidad de conducción motora estaba ligeramente disminuida. El resto de los exámenes fueron normales. No se detectaron alteraciones de la inmunidad humoral ni celular. La biopsia de nervio safeno externo mostró disminución de fibras mielínicas gruesas y medianas, variables según los fascículos, hasta alrededor de un 40 por ciento, con aisladas fibras en degeneración actual, sin evidencias de regeneración axonal. En los cortes semifinos y en el estudio ultraestructural se confirmaron los hallazgos ópticos y las fibras remanentes no mostraron alteraciones axonales ni en las células de Schwann. Estos hallazgos son compatibles con afectación de las neuromas sensitivas primarias del ganglio de la raíz dorsal, como ha sido previamente descripto en esta enfermedad y son comparables a las lesiones vistas en otras afectaciones ganglionares (degeneraciones espino-cerebelosas-Friedreich); por lo tanto, desde el punto de vista neurológico y neuropatológico, creemos conveniente ubicar este síndrome dentro de las degeneraciones espino-cerebelosas, como ya fuera propuesto por E. Boder y R. P. Sedgwick (AU)
Subject(s)
Child , Humans , Male , Ataxia Telangiectasia/physiopathology , Myelin Sheath/ultrastructure , Sural Nerve/pathology , Atrophy , Cerebrum/pathologyABSTRACT
La neuropatía periférica correspondiente al síndrome de ataxia telangiectasia es poco conocida. Se presenta un caso en un niño de 9 años de edad, con antecedentes familiares de padre, madre y hermanos con telangiectasias conjuntivales. A la edad de tres años comienza con signos centrales, caídas frecuentes, babeo y temblores en miembros superiores, estrabismo convergente de ojo derecho y nistagmus lateral y vertical. Al examen neurológico se encuentra hipotrofia muscular en ambas piernas, con caída de ambos antepiés, arreflexia en miembros inferiores y sensibilidad superficial y profunda conservada. Se detectó atrofia cerebelosa por tomografía computada y la velocidad de conducción motora estaba ligeramente disminuida. El resto de los exámenes fueron normales. No se detectaron alteraciones de la inmunidad humoral ni celular. La biopsia de nervio safeno externo mostró disminución de fibras mielínicas gruesas y medianas, variables según los fascículos, hasta alrededor de un 40 por ciento, con aisladas fibras en degeneración actual, sin evidencias de regeneración axonal. En los cortes semifinos y en el estudio ultraestructural se confirmaron los hallazgos ópticos y las fibras remanentes no mostraron alteraciones axonales ni en las células de Schwann. Estos hallazgos son compatibles con afectación de las neuromas sensitivas primarias del ganglio de la raíz dorsal, como ha sido previamente descripto en esta enfermedad y son comparables a las lesiones vistas en otras afectaciones ganglionares (degeneraciones espino-cerebelosas-Friedreich); por lo tanto, desde el punto de vista neurológico y neuropatológico, creemos conveniente ubicar este síndrome dentro de las degeneraciones espino-cerebelosas, como ya fuera propuesto por E. Boder y R. P. Sedgwick
