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1.
Front Endocrinol (Lausanne) ; 12: 723750, 2021.
Article in English | MEDLINE | ID: mdl-34539576

ABSTRACT

Genetic defects in the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) result in MCT8 deficiency. This disorder is characterized by a combination of severe intellectual and motor disability, caused by decreased cerebral thyroid hormone signalling, and a chronic thyrotoxic state in peripheral tissues, caused by exposure to elevated serum T3 concentrations. In particular, MCT8 plays a crucial role in the transport of thyroid hormone across the blood-brain-barrier. The life expectancy of patients with MCT8 deficiency is strongly impaired. Absence of head control and being underweight at a young age, which are considered proxies of the severity of the neurocognitive and peripheral phenotype, respectively, are associated with higher mortality rate. The thyroid hormone analogue triiodothyroacetic acid is able to effectively and safely ameliorate the peripheral thyrotoxicosis; its effect on the neurocognitive phenotype is currently under investigation. Other possible therapies are at a pre-clinical stage. This review provides an overview of the current understanding of the physiological role of MCT8 and the pathophysiology, key clinical characteristics and developing treatment options for MCT8 deficiency.


Subject(s)
Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/therapy , Muscle Hypotonia/genetics , Muscle Hypotonia/therapy , Muscular Atrophy/genetics , Muscular Atrophy/therapy , Humans , Mental Retardation, X-Linked/mortality , Mental Retardation, X-Linked/pathology , Monocarboxylic Acid Transporters/genetics , Muscle Hypotonia/mortality , Muscle Hypotonia/pathology , Muscular Atrophy/mortality , Muscular Atrophy/pathology , Phenotype , Signal Transduction/genetics , Symporters/genetics , Therapies, Investigational/methods , Therapies, Investigational/trends
2.
J Hum Genet ; 65(9): 751-757, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32405030

ABSTRACT

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.


Subject(s)
Brain Diseases/genetics , Developmental Disabilities/genetics , Epilepsy/genetics , Genetic Predisposition to Disease , Multiple Organ Failure/genetics , Muscle Hypotonia/genetics , Pyrophosphatases/genetics , Brain Diseases/complications , Brain Diseases/enzymology , Brain Diseases/mortality , Corpus Callosum/diagnostic imaging , Corpus Callosum/pathology , Developmental Disabilities/complications , Developmental Disabilities/enzymology , Developmental Disabilities/mortality , Epilepsy/complications , Epilepsy/enzymology , Epilepsy/mortality , Female , Genotype , Homozygote , Humans , Infant , Magnetic Resonance Imaging , Male , Multiple Organ Failure/complications , Multiple Organ Failure/enzymology , Multiple Organ Failure/mortality , Muscle Hypotonia/complications , Muscle Hypotonia/enzymology , Muscle Hypotonia/mortality , Mutation , Pedigree , Pyramidal Tracts/diagnostic imaging , Pyramidal Tracts/pathology , Exome Sequencing
3.
Am J Med Genet A ; 182(3): 504-507, 2020 03.
Article in English | MEDLINE | ID: mdl-31746132

ABSTRACT

Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non-convulsive status epilepticus and epileptic spasms after three first-line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival.


Subject(s)
Fumarate Hydratase/deficiency , Fumarate Hydratase/genetics , Metabolism, Inborn Errors/genetics , Muscle Hypotonia/genetics , Psychomotor Disorders/genetics , Spasms, Infantile/genetics , Brain/pathology , Child , Female , Humans , Infant, Newborn , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/mortality , Muscle Hypotonia/diagnosis , Muscle Hypotonia/mortality , Mutation/genetics , Psychomotor Disorders/diagnosis , Psychomotor Disorders/mortality , Seizures/diagnosis , Seizures/genetics , Seizures/mortality , Spasms, Infantile/diagnosis , Spasms, Infantile/mortality
4.
Duodecim ; 130(21): 2202-5, 2014.
Article in Finnish | MEDLINE | ID: mdl-25582014

ABSTRACT

Normal function of the thyroid gland is the cornerstone of a child's mental development and physical growth. We describe a Finnish family, in which the diagnosis of three brothers became clear after investigations that lasted for more than 30 years. Two of the sons have already died. DNA analysis of the third one, a 16-year-old boy, revealed in exome sequencing of the complete X chromosome a mutation in the SLC16A2 gene, i.e. MCT8, coding for a thyroid hormone transport protein. Allan-Herndon-Dudley syndrome was thus shown to be the cause of multiple disabilities.


Subject(s)
Mental Retardation, X-Linked/genetics , Monocarboxylic Acid Transporters/genetics , Muscle Hypotonia/genetics , Muscular Atrophy/genetics , Adolescent , Chromosomes, Human, X , Exome , Finland , Humans , Male , Mental Retardation, X-Linked/mortality , Muscle Hypotonia/mortality , Muscular Atrophy/mortality , Mutation , Pedigree , Sequence Analysis, DNA , Symporters
5.
J Ayub Med Coll Abbottabad ; 19(1): 26-8, 2007.
Article in English | MEDLINE | ID: mdl-17867475

ABSTRACT

BACKGROUND: Acute flaccid paralysis (AFP) can be caused by a number of conditions. A common preventable cause is poliomyelitis which is still being reported in Pakistan, Guillain Barre Syndrome (GBS), also known as Acute Inflammatory Demyelinating Polyneuropathy, is another common cause of acute flaccid paralysis. It is important to recognize GBS in childhood as parents consider all acute flaccid paralysis to be due to poliomyelitis. The present study was designed to know the frequency of different causes of acute flaccid paralysis in Hazara division. METHODS: This is a retrospective analysis of cases of acute flaccid paralysis reported from various districts of Hazara division during the period January 2003 to December 2004. Acute flaccid paralysis was diagnosed clinically through history and clinical examination. The underlying cause of acute flaccid paralysis was investigated by appropriate laboratory tests, such as serum electrolytes, cerebrospinal fluid analysis, electromyogram, nerve conduction study and stool culture for polio virus and other enteroviruses. Diagnosis of Poliomyelitis was confirmed by stool testing for poliovirus. RESULTS: 74 patients presented with AFP during the study period. 36 were male and 38 were female. Guillain Barre syndrome and enteroviral encephalopathy were the two leading causes of acute flaccid paralysis. Majority of the cases were reported from Mansehra district. Children of age groups 12 to 24 months and > 96 months constituted the majority (20% each). CONCLUSION: Guillian Barre syndrome was the leading cause of acute flaccid paralysis reported from various parts of Hazara division.


Subject(s)
Guillain-Barre Syndrome/complications , Muscle Hypotonia/etiology , Paraplegia/etiology , Acute Disease , Age Factors , Child , Child, Preschool , Female , Humans , Infant , Male , Muscle Hypotonia/epidemiology , Muscle Hypotonia/mortality , Pakistan/epidemiology , Paraplegia/epidemiology , Paraplegia/mortality , Retrospective Studies , Risk Factors
6.
J Perinatol ; 26(4): 237-42, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16496014

ABSTRACT

OBJECTIVE: The incidence of acute neurologic events prior to discharge in neonates with congenital heart disease (CHD) was determined and peri-operative characteristics predictive of a neurologic event were identified. STUDY DESIGN: A retrospective chart review over 1 year was conducted of infants <1 month of age with a diagnosis of CHD. Outcomes were measured by the occurrence of an acute neurologic event defined as electroencephalogram (EEG)-proven seizure activity, significant hypertonia or hypotonia, or choreoathetosis prior to hospital discharge. Stepwise logistic regression identified variables most likely to be associated with an acute neurologic event. RESULTS: Surgical intervention occurred in 95 infants who were admitted with a diagnosis of CHD. The survival rate was 92%. Of the survivors, 16 (17%) had an acute neurologic event, with 19% of events occurring preoperatively. Factors associated with neurologic events included an elevated nucleated red blood cell (NRBC) count, an abnormal preoperative brain imaging study, and a 5-min Apgar score <7 (P<0.05). CONCLUSIONS: Neonates with CHD have a significant risk of neurologic events. Preoperative brain imaging, the 5-min Apgar score, and initial serum NRBC counts may identify infants at highest risk for central nervous system injury.


Subject(s)
Athetosis/etiology , Chorea/etiology , Heart Defects, Congenital/surgery , Muscle Hypertonia/etiology , Muscle Hypotonia/etiology , Postoperative Complications/etiology , Seizures/etiology , Acute Disease , Athetosis/mortality , Chorea/mortality , Electroencephalography , Female , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/mortality , Humans , Infant, Newborn , Male , Muscle Hypertonia/mortality , Muscle Hypotonia/mortality , Neurologic Examination , Postoperative Complications/mortality , Retrospective Studies , Risk Factors , Seizures/mortality , Survival Rate
7.
Ter Arkh ; 75(6): 50-3, 2003.
Article in Russian | MEDLINE | ID: mdl-12920960

ABSTRACT

AIM: To study causes and sequelae of intradialysis hypotension (IH) in patients with terminal renal failure (TRF). MATERIAL AND METHODS: Forty one patients with TRF on chronic hemodialysis (CH) were divided into two groups. The study group consisted of 24 patients with episodes of IH. Seventeen patients of the control group had no IH. All the patients were examined with assessment of protein-energy deficiency, residual renal function, left-ventricular hypertrophy, diastolic function of the heart. Hemodialysis effectiveness was estimated by Kt/V index. Survival of the patients was calculated according to Kaplan-Meier method. RESULTS: In the study group IH episodes occurred in spite of low ultrafiltration velocity (8-10 ml/min). Those patients of the study group who had IH associated with polyneuropathy and left-ventricular hypertrophy had IH episodes more often and sharper falls of arterial pressure. Long-term IH decreased survival significantly. CONCLUSION: Repeated episodes of IH deteriorate effectiveness of hemodialysis because of acute coronary syndrome, acute disorder of cerebral circulation, complications of deficient dialysis syndrome (pericarditis, hyperkaliemia, pulmonary edema, congestive heart failure).


Subject(s)
Kidney Failure, Chronic/therapy , Muscle Hypotonia/etiology , Renal Dialysis/adverse effects , Adolescent , Adult , Aged , Female , Glomerular Filtration Rate/physiology , Humans , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/physiopathology , Male , Middle Aged , Muscle Hypotonia/mortality , Risk Factors , Survival Analysis
8.
Acta Paediatr Jpn ; 34(2): 139-43, 1992 Apr.
Article in English | MEDLINE | ID: mdl-1621519

ABSTRACT

The histological and histochemical findings in the respiratory muscles of a patient with severe neonatal nemaline myopathy are described. The patient suffered from frequent pneumonia associated with vomiting due to gastroesophageal reflux and died at 3 months from respiratory failure. The diaphragm was moderately involved and the intercostal muscles mildly involved. Core/targetoid structures were observed in the diaphragm and intercostal muscles.


Subject(s)
Respiration Disorders/physiopathology , Respiratory Insufficiency/mortality , Respiratory Muscles/pathology , Comorbidity , Humans , Infant, Newborn , Infant, Newborn, Diseases , Male , Muscle Hypotonia/mortality , Muscle Hypotonia/physiopathology , Respiration Disorders/etiology , Respiration Disorders/mortality , Respiratory Muscles/ultrastructure
9.
Arch Pathol Lab Med ; 103(1): 1-5, 1979 Jan.
Article in English | MEDLINE | ID: mdl-581546

ABSTRACT

Two infant siblings (male and female) manifested extreme hypotonia and flaccidity at birth and had a rapidly fatal course. In each, rod-like structures were demonstrated within a variety of skeletal muscles, and accumulations of thin filaments were seen in numerous muscle fibers. The possibility exists that this represents a severe and rapidly fatal form of nemaline myopathy that should be included in the differential diagnosis of infantile hypotonias.


Subject(s)
Infant, Newborn, Diseases/pathology , Muscle Hypotonia/pathology , Muscles/ultrastructure , Biopsy , Cytoplasmic Granules/ultrastructure , Female , Humans , Infant, Newborn , Male , Muscle Hypotonia/etiology , Muscle Hypotonia/mortality , Muscular Atrophy/pathology , Respiratory Distress Syndrome, Newborn/pathology , Sarcolemma/ultrastructure
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