Prenatal Treatment of Thyroid Hormone Cell Membrane Transport Defect Caused by MCT8 Gene Mutation.

Background: Mutations of the thyroid hormone (TH)-specific cell membrane transporter, monocarboxylate transporter 8 (MCT8), produce an X-chromosome-linked syndrome of TH deficiency in the brain and excess in peripheral tissues. The clinical consequences include brain hypothyroidism causing severe psychoneuromotor abnormalities (no speech, truncal hypotonia, and spastic quadriplegia) and hypermetabolism (poor weight gain, tachycardia, and increased metabolism, associated with high serum levels of the active TH, T3). Treatment in infancy and childhood with TH analogues that reduce serum triiodothyronine (T3) corrects hypermetabolism, but has no effect on the psychoneuromotor deficits. Studies of brain from a 30-week-old MCT8-deficient embryo indicated that brain abnormalities were already present during fetal life. Methods: A carrier woman with an affected male child (MCT8 A252fs268*), pregnant with a second affected male embryo, elected to carry the pregnancy to term. We treated the fetus with weekly 500 µg intra-amniotic instillation of levothyroxine (LT4) from 18 weeks of gestation until birth at 35 weeks. Thyroxine (T4), T3, and thyrotropin (TSH) were measured in the amniotic fluid and maternal serum. Treatment after birth was continued with LT4 and propylthiouracil. Follow-up included brain magnetic resonance imaging (MRI) and neurodevelopmental evaluation, both compared with the untreated brother. Results: During intrauterine life, T4 and T3 in the amniotic fluid were maintained above threefold to twofold the baseline and TSH was suppressed by 80%, while maternal serum levels remained unchanged. At birth, the infant serum T4 was 14.5 µg/dL and TSH <0.01 mU/L compared with the average in untreated MCT8-deficient infants of 5.1 µg/ and >8 mU/L, respectively. MRI at six months of age showed near-normal brain myelination compared with much reduced in the untreated brother. Neurodevelopmental assessment showed developmental quotients in receptive language and problem-solving, and gross motor and fine motor function ranged from 12 to 25 at 31 months in the treated boy and from 1 to 7 at 58 months in the untreated brother. Conclusions: This is the first demonstration that prenatal treatment improved the neuromotor and neurocognitive function in MCT8 deficiency. Earlier treatment with TH analogues that concentrate in the fetus when given to the mother may further rescue the phenotype.

Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome.

PURPOSE: We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. OBSERVATIONS: After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. CONCLUSIONS AND IMPORTANCE: Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography.

Mutations in γ adducin are associated with inherited cerebral palsy.

OBJECTIVE: Cerebral palsy is estimated to affect nearly 1 in 500 children, and although prenatal and perinatal contributors have been well characterized, at least 20% of cases are believed to be inherited. Previous studies have identified mutations in the actin-capping protein KANK1 and the adaptor protein-4 complex in forms of inherited cerebral palsy, suggesting a role for components of the dynamic cytoskeleton in the genesis of the disease. METHODS: We studied a multiplex consanguineous Jordanian family by homozygosity mapping and exome sequencing, then used patient-derived fibroblasts to examine functional consequences of the mutation we identified in vitro. We subsequently studied the effects of adducin loss of function in Drosophila. RESULTS: We identified a homozygous c.1100G>A (p.G367D) mutation in ADD3, encoding gamma adducin in all affected members of the index family. Follow-up experiments in patient fibroblasts found that the p.G367D mutation, which occurs within the putative oligomerization critical region, impairs the ability of gamma adducin to associate with the alpha subunit. This mutation impairs the normal actin-capping function of adducin, leading to both abnormal proliferation and migration in cultured patient fibroblasts. Loss of function studies of the Drosophila adducin ortholog hts confirmed a critical role for adducin in locomotion. INTERPRETATION: Although likely a rare cause of cerebral palsy, our findings indicate a critical role for adducins in regulating the activity of the actin cytoskeleton, suggesting that impaired adducin function may lead to neuromotor impairment and further implicating abnormalities of the dynamic cytoskeleton as a pathogenic mechanism contributing to cerebral palsy.

Chronic hip pain in a boy with mental retardation and cerebral palsy.

CASE: Jonny is a 13 year old boy with spastic quadriparesis and severe mental retardation following Haemophilus influenza type B (HIB) meningitis at 2-months of age. Signs of meningitis started on the evening of his 2-month immunizations that included the HIB vaccine. He presented to his pediatrician with left hip pain that occurred intermittently for a few years and more frequently in the past six months. His parents initially attributed the pain to whizzing around the back yard in a motorized wheelchair. An earlier evaluation of hip pain led to bilateral femoral osteotomies for hip dysplasia. Obesity, associated with inactivity and a tendency to consume fatty foods, complicates Jonny's disabilities. His only activity is a modest amount of physical therapy at school and "floor time" for about one hour each day at home. In the office of his pediatrician, Jonny is friendly, smiling, and verbalizing a few words with his limited expressive vocabulary. He is resistant to a hip examination and grimaces with manipulation of his left hip. Spasticity of the left leg appears increased compared to previous examinations. He has nonpitting edema of his lower legs and feet, a cryptorchid left testicle, and a somewhat tender left inguinal area. Jonny lives with his mother and father in a small house on a busy street less than one-half mile from the pediatrician's office. Jonny's pediatrician often sees him in his wheelchair, accompanied by his mother or grandmother, and waves or stops to chat. He has van services to school, and there is a Hoyer lift in the home, but his parents do not own a van. Recently, Jonny's father finds it more difficult to lift him. The family has also been challenged by the mental health problems of Jonny's two older brothers, and a serious eye injury suffered by his middle brother in a motor-vehicle accident. Jonny's pediatrician has cared for him and his two brothers since birth. Although the parents continue to believe that the HIB vaccine caused his catastrophic illness, they remain with the pediatrician. In general, they are satisfied with the individualized educational plan at a local public school. When he was 6.5 years old, Jonny's school aid reported that he attempted to touch her in the genital area. The pediatrician attended the meeting to review this incident and successfully advocated for Jonny by pointing out that this was an isolated incident; it did not occur again. At 6 years old Jonny functioned in the 1.5-2.5 year old range with motor skills in the 6-12 month level according to the Bayley Scales of Infant Development and the Vineland Adaptive Behavior Scales. In the past a neurologist and a physiatrist saw Jonny, but both of these individuals moved from the community. He had prior evaluations at a children's orthopedic clinic at a small community hospital and at the local Shriner's hospital. He had a tonsillectomy and adenoidectomy at 7 years old. He is currently treated for constipation and receives dental care at a clinic for people with disabilities. His pediatrician has always respected the parents for their care and obvious love for their disabled child. However, parental resistance to addressing major issues such as obesity has frustrated his pediatrician. When the pediatrician suggested that Jonny was eligible for the state's managed care program, which would convert Medicaid coverage to a state sponsored program with more extensive services and case management, Jonny's mother repeatedly said that she would "think it over." At the current visit, the pediatrician recommended an adjustment of Jonny's wheelchair, a hip x-ray, a referral to Shriner's Hospital, and an appointment with a pediatric surgeon to address the undescended testicle and possible hernia. Jonny's mother mentioned that he had been to Shriner's Hospital for hip pain two years earlier but was told nothing could be done "because nothing was wrong with his bone." The hip x-ray was normal as well as a complete blood count and a C-reactive protein. The pediatric surgeon did not find a hernia and deferred treatment of the cryptorchid testicle. His parents contacted the wheelchair company to arrange adjustments. The pediatrician called the medical director at the Shriner's Hospital to discuss Jonny's case, but 2 months after the initial visit, the parents had not arranged for an appointment at the Shriner's Hospital. Jonny's hip pain persisted. The pediatrician now wonders how he can more effectively address Jonny's current problems and improve overall care for him and his family.

Truncal ataxia, hypotonia, and motor delay with isolated rhombencephalosynapsis.

We report on a 16-month-old girl with developmental motor delay, microcephaly, and mild truncal ataxia who was revealed to have rhombencephalosynapsis on magnetic resonance imaging. The child was nonsyndromic and exhibited normal cognitive and social abilities for her age, despite neuroimaging findings. As this case demonstrates, motor skills in children with isolated rhombencephalosynapsis may be relatively mildly affected, and cognition may be normal despite the presence of a major central nervous system anomaly. Neuroimaging may be helpful in defining the nature of a child's deficits at an early age, particularly when associated with microcephaly and abnormalities on neurologic examination.

Validation of a care and comfort hypertonicity questionnaire.

The lack of evidence regarding functional and quality of life benefits resulting from tone reduction with intrathecal baclofen (ITB) infusion treatment relates to the lack of validated and responsive measures. We integrated our scale/questionnaire, developed from chart review, with the non-validated Caregiver Questionnaire (CQ) to yield a final document, the Care and Comfort Hypertonicity Questionnaire (CCHQ). Convergent validity was achieved by administering the CCHQ to 47 patients with spastic/dystonic cerebral palsy (CP) who were being evaluated for tone management. The population studied included 18 females and 29 males (mean age 10y [SD 4y 10mo]; range 3y 1mo-21y 1mo). Twenty-five patients were subsequently referred for botulinum toxin (BTX-A) injections (mean Gross Motor Function Classification System [GMFCS] 3.2); 11 patients were referred for ITB (mean GMFCS 4.4); four were referred for orthopedic surgery (mean GMFCS 3.3); 3 were referred for selective dorsal rhizotomy (mean GMFCS 2.7); one was recommended for oral baclofen (GMFCS 5); and three were recommended for no treatment (mean GMFCS 3.7). Blinded to the score, those with the highest scores (severe hypertonicity) were recommended for ITB; those with the lowest scores were recommended for BTX-A injections. Responsiveness of the CCHQ was established by administering the questionnaire to patients who already had an implanted ITB pump. The children with the largest dose increase demonstrated a statistically significant improvement in the CCHQ score. This scale can be used to document the efficacy of treating severe hypertonicity both in clinical and research protocols.