Clinical Features

In 1944, a large family with X- linked intellectual disability was described by Allan, Herndon, and Dudley, with this and subsequent similar cases being designated an eponymous (Allan- Herndon- Dudley) syndrome (AHDS). Many decades later AHDS patients were noted to have abnormal thyroid function tests.

Patients with AHDS are usually born at term from uncomplicated pregnancy with normal birthweight. Generalized muscular hypotonia is a feature in early neonatal life, with persistent truncal hypotonia being associated with poor head control; peripherally, hypotonia progresses into spasticity with hyperreflexia, clonus, and extensor plantar responses. Poor motor development usually precludes ability of patients to sit, stand, or walk; cognitive impairment (IQ <40) limits speech severely, but patients retain awareness of surroundings with smiling and crying; hearing and vision are typically unaffected. Epilepsy, ranging from absence to tonic- clonic seizures, occurs in 25% of cases. Involuntary movements (dystonic, choreoathetoid, ballismus), sometimes occurring in paroxysms triggered by external stimuli, are a further characteristic. Progressive microcephaly is associated with reduced head circumference. Brain MRI in early life (<2 years) shows reduced myelination but this normalizes by 4 years of age, distinguishing this disorder from other hypomyelinating leukodystrophies (e.g. Pelizaeus– Merzbacher disease). Although linear growth is pre served, body weight is usually extremely low in AHDS patients despite gastrostomy feeding to overcome swallowing difficulties; proximal muscle wasting is an added contributory factor. Somatic features include elongated myopathic facies and a tented upper lip due to hypotonia. Some patients exhibit a milder neuro logical phenotype, walking with ataxic gait and being capable of dysarthric speech.

AHDS patients exhibit reduced circulating free T4, raised free T3, normal or mildly elevated TSH, and subnormal reverse T3 levels; consequently, circulating T3/ rT3 ratios are raised. Serum levels of sex hormone- binding globulin (SHBG), a hepatic marker of thyroid action, are markedly elevated; in addition, ammonemia and raised lactic acid levels, signifying a catabolic state, has been documented. These biochemical features support the notion of a relative hyperthyroid state in peripheral tissues of MCT8- deficient patients.

Molecular Genetics and Pathogenesis

 Consistent with the male- limited nature of the disorder, AHDS is due to defects in the monocarboxylate transporter 8 (MCT8, SLC16A2) gene located on chromosome Xq13.2. Over 70 different MCT8 mutations (deletions, frameshift/ premature stop, missense) have been identified in ~100 families from di verse ethnic backgrounds, with complete penetrance in males and occurring de novo in ~25% of cases. When expressed in cells the majority of MCT8 mutants exhibit complete loss- of- function, with failure of TH transport; however, some missense mutants show residual transport capacity, which may correlate with a milder clinical phenotype in patients. Female carriers are fertile with normal neurocognitive and thyroid function, but in rare cases it is possible that skewed X- inactivation leading to MCT8 deficiency could mediate a phenotype.

MCT8 is expressed in many tissues, including brain, liver, kidney, heart, thyroid and placenta; in murine brain MCT8 is found predominantly in neurons and coexpressed with DIO3 which catabolizes T3, whereas DIO2 mediating T4 to T3 conversion is largely expressed in adjacent astrocytes and glial cells; accordingly, one theory is that MCT8- mediated neuronal uptake of T3, generated by surrounding, DIO2- containing, astrocytes, maintains euthyroid status of the CNS. Alternatively, a study using patient- derived stem cells has suggested that the key defect is loss of MCT8- mediated T3 transport across the endothelial blood- brain barrier.

Management

General supportive measures include use of braces or baclofen to prevent joint contractures; gastrostomy feeding to prevent aspiration and catabolic weight loss; counteracting dystonia with anticholinergic agents or L- DOPA; reducing hypersalivation with glycopyrrolate or scopolamine; and anticonvulsants to treat seizure activity.

Specific treatment approaches include normalization of TH levels with a ‘block and replace’ combination of propylthiouracil and T4. Treatment of older AHDS patients has targeted increased body weight and reduced heart rate.

An alternative approach involves administration of a thyroid hormone analogue whose CNS uptake is MCT8- independent. Diiodothyropropionic acid (DITPA) has been used in four, younger, AHDS patients, with normalization of circulating TH levels, weight gain, and reduction in heart rate. 3,5,3’- triiodothyroacetic acid (TRIAC), another TH analogue, has been trialled in AHDS patients (ClinicalTrials.gov NCT02060474), with preliminary results showing normalization of fT3 levels and alleviation of peripheral hyperthyroidism.

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم رعاية الصحن الشريف ينشر لافتات الحزن بذكرى شهادة الإمام الجواد (عليه السلام)

قسم العلاقات العامة يقيم مجلس عزائه الأسبوعي لاستذكار فضائل أهل البيت (عليهم السلام)

متحف الكفيل يستعرض درعًا هنديًّا يعود إلى القرن التاسع عشر

ضمن محفلها الأسبوعيّ.. دار علوم نهج البلاغة تقدّم محاضرةً عن تحرير الإنسان من قيود المنصب

المزيد

الآخبار الصحية

طريقة مبتكرة للكشف المبكر عن أمراض القلب والشرايين

منظمة الصحة تحذر من خطر إدمان الشباب لأكياس النيكوتين

خبراء يحذرون من عادة شائعة تهدد صحة الملايين

خبير يكشف 5 حقائق طبية صادمة وغير معروفة

المزيد

الآخبار التكنلوجية

الأولى في العالم.. الصين تجري تجربة رائدة في الفضاء باستخدام "جنين اصطناعي"

دراسة حديثة تفند ربط التستوستيرون بالمخاطرة لدى الرجال

ميتا تضيف وضع "المحادثة المخفية" إلى تطبيق "واتساب"

فوبيا المرتفعات ليست من الدماغ.. دراسة تكشف السبب

المزيد

مواضيع ذات صلة

Resistance to Thyroid Hormone Beta

Selenoprotein Deficiency— A Disorder of Thyroid Hormone Metabolism

Glucose Phosphate Isomerase Deficiency

Pyruvate Kinase Deficiency

Complications of Thalassemia and Their Management: Endocrinopathies

Complications of Thalassemia and Their Management: Skeletal Changes

Complications of Thalassemia and Their Management : Complications Related to Ineffective Erythropoiesis

Glucose-6-Phosphate Dehydrogenase Deficiency

Pathobiology of Sickle Cell Disease : Disease pathogenesis

Alpha-Thalassemia Syndromes

Acute Intermittent Porphyria

Porphyrias: Genetic Aspects