Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

OBJECTIVE: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. METHODS: Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. RESULTS: The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. INTERPRETATION: This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency.

We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.

Age at disease onset predicts likelihood and rapidity of growth failure among infants and young children with spinal muscular atrophy types 1 and 2.

Growth failure is nearly universal in spinal muscular atrophy type 1 and common in type 2, although acuity is often underappreciated at initial diagnosis. We reviewed 44 consecutive spinal muscular atrophy patients (28 type 1, 16 type 2) under 3 years at initial presentation. Growth failure was conventionally defined: weight below the fifth percentile or dropping 2 major percentiles over 6 months. Growth failure differed among subjects stratified by age at disease onset using the Kaplan-Meier method (P = 0.011). Median time to growth failure among subjects with onset between 0 to 3 months of age was 5 months; Only 1 of 22 avoided failure by 22 months of age. Median time to failure with disease onset between 4 to 6 months was 15 months. Most late onset (> 6 months) subjects avoided growth failure. Early clinical symptoms predict feeding dysfunction and growth failure. Immediate, proactive nutritional intervention is indicated for patients with early symptom onset.

Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy.

The relationship between body composition and function in spinal muscular atrophy (SMA) is poorly understood. 53 subjects with SMA were stratified by type and Hammersmith functional motor scale, expanded score into three cohorts: low-functioning non-ambulatory (type 2 with Hammersmith score < 12, n=19), high-functioning non-ambulatory (type 2 with Hammersmith score > or = 12 or non-ambulatory type 3, n=17), and Ambulatory (n=17). Lean and fat mass was estimated using dual-energy X-ray absorptiometry. Anthropometric data was incorporated to measure fat-free (lean mass in kg/stature in m(2)) and fat (fat mass in kg/stature in m(2)) mass indices, the latter compared to published age and sex norms. Feeding dysfunction among type 2 subjects was assessed by questionnaire. Fat mass index was increased in the high-functioning non-ambulatory cohort (10.4+/-4.5) compared with both the ambulatory (7.2+/-2.1, P=0.013) and low-functioning non-ambulatory (7.6+/-3.1, P=0.040) cohorts. 12 of 17 subjects (71%) in the high-functioning non-ambulatory cohort had fat mass index > 85th percentile for age and gender (connoting "at risk of overweight") versus 9 of 19 subjects (47%) in the low-functioning non-ambulatory cohort and 8 of 17 ambulatory subjects (47%). Despite differences in clinical function, a similar proportion of low functioning (7/18, 39%) and high functioning (2/7, 29%) type 2 subjects reported swallowing or feeding dysfunction. Non-ambulatory patients with relatively high clinical function may be at particular risk of excess adiposity, perhaps reflecting access to excess calories despite relative immobility, emphasizing the importance of individualized nutritional management in SMA.

Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy.

Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m(2)), fat-free (FFMI, lean mass/height in m(2)) and fat (FMI, fat mass/height in m(2)) mass indexes were estimated in 25 children (aged 5-18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was 50th percentile in 11 (44%) and 85th in 5 (20%). FFMI was reduced (p<0.005) and FMI was increased (p<0.005) in the overall study cohort. FMI was 50th, 85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75th, 50th and 3rd percentiles maximized sensitivity and specificity for FMI 95th, 85th and 50th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA.

Protean phenotypic features of the A3243G mitochondrial DNA mutation.

OBJECTIVE: To describe the spectrum of clinical symptoms, signs, and laboratory features associated with A3243G, a mitochondrial DNA point mutation that affects multiple organs with varying severity, making the diagnosis and treatment of these patients complex. DESIGN: Cohort study. SETTING: Columbia University Medical Center. PARTICIPANTS: A cohort of 123 matrilineal relatives from 45 families, including 45 fully symptomatic patients with mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (syndrome), 78 carrier relatives, and 30 controls. MAIN OUTCOME MEASURES: Data gathered from standardized medical history questionnaires, neurological and ophthalmological examination forms, and laboratory tests. We compared data between 3 groups. RESULTS: Mutation carriers' clinical and laboratory results frequently had many abnormalities. In addition to neurological symptoms, they often had cardiac, endocrine, gastrointestinal, and psychiatric symptoms. CONCLUSIONS: The A3243G mutation carriers have multiple medical problems, suggesting that the A3243G mutation should be considered as an etiological factor in patients with multisystem clinical presentations or a family history compatible with matrilineal inheritance. Because some medical problems affecting A3243G mutation carriers are treatable, early detection and proactive management may mitigate the burden of morbidity.