A 19-month-old girl was born after a normal full-term pregnancy. There was no family history of autism or affective, neuromuscular, or hearing disorders. Her development was progressing well, with normal receptive and expressive language and use of prelinguistic gestures, such as pointing for joint attention. Imaginary play and social reciprocity were typical for age. She used at least 20 words and could point to five body parts on command. Several immunizations were delayed owing to frequent bouts of otitis media with fever.
Within 48 hours after immunizations to diphtheria, tetanus, and pertussis; Haemophilus influenzae B; measles, mumps, and rubella; polio; and varicella (Varivax), the patient developed a fever to 38.9°C, inconsolable crying, irritability, and lethargy and refused to walk. Four days later, the patient was waking up multiple times in the night, having episodes of opistho-tonus, and could no longer normally climb stairs. Instead, she crawled up and down the stairs. Low-grade intermittent fever was noted for the next 12 days. Ten days following immunization, the patient developed a generalized erythematous macular rash beginning in the abdomen. The patient’s pediatrician diagnosed this as due to varicella vaccination. For 3 months, the patient was irritable and increasingly less responsive verbally, after which the patient’s family noted clear autistic behaviors, such as spinning, gaze avoidance, disrupted sleep/wake cycle, and perseveration on specific television programs. All expressive language was lost by 22 months. The patient continued to have chronic yellow watery diarrhea intermittently for 6 months, which was evaluated with negative testing for Clostridium difficile, ova/parasites, and culture. Four months later, an evaluation with the Infant and Toddlers Early Intervention program for possible autism was initiated. Along with the regression, her appetite remained poor for 6 months and her body weight did not increase. This resulted in a decline on a standard growth chart for weight from the 97th to the 75th percentile.
Evaluation at 23 months showed atopic dermatitis, slow hair growth, generalized mild hypotonia, toe walking, and normal tendon reflexes. The Childhood Autism Rating Scale (CARS) score was 33 (mild autism range), and she also met Diagnostic and Statistical Manual for Mental Disorders-IV criteria for autism. Laboratory findings included repeated measurements of aspartate aminotransferase 40 IU/L (normal < 31 IU/L), serum bicarbonate 20 mmol/L (normal 21–31 mmol/L), serum creatine kinase level 203 IU/L (normal < 170 IU/L), and fasting lactic acid 3.3 mmol/L (normal 0.5–2.2 mmol/L). Quantitative urinary organic acid analyses showed trace amounts of dicarboxylic acids (adipic, suberic, octenedioic acids) and small amounts of ethylmalonic and methylsuccinic acids, consistent with a fatty acid oxidation dysfunction. Quantitative plasma amino acids were all within the normal range; however, the alanine to lysine ratio (a surrogate marker for pyruvate; Dr Richard Kelley, personal communication, 2001) was elevated at 3.2 (normal 1.5–2.5). Cranial magnetic resonance imaging, otoacoustic emission testing, overnight electroencephalography with slow-wave sleep, serum lead, chromosomes, and fragile X by DNA testing were all normal.
The patient was referred for muscle biopsy (J.S.) because of persistent mild lactic acidosis, elevated serum creatine kinase level, and increased aspartate aminotransferase. A fresh vastus lateralis biopsy was performed and examined as described previously.7,8
The biopsy showed abnormal histology with type I myofiber atrophy, increased myofiber lipid content, and reduced cytochrome c oxidase activity. Oxidative phosphorylation enzymology showed markedly reduced complex I, I + III, and III activity. Complex IV activity was near the 5% confidence limit of the control group (). Mitochondrial DNA sequencing of the skeletal muscle was normal.
Skeletal Muscle Oxidative Phosphorylation Enzymology Results
Now 6 years old, our patient has been treated with vitamin supplements since 2½ years of age. Even before starting supplementation, the patient began speaking again at 23 months old and had a four-word vocabulary of “bubbles,” “ball,” “drink,” and “cracker.” Levocarnitine 250 mg and thiamine 50 mg three times per day were initiated when the patient was 29 months old. Coenzyme Q10 was added at age 33 months. Although she still exhibits mild autistic behaviors, our patient has continued to improve in language functions and sociability such that she now attends a regular kindergarten with an aide. There have been slow yet steady improvements in muscle tone, motor coordination, and gastrointestinal symptoms with occupational therapy, applied behavioral analysis interventions, and mitochondrial enzyme cofactor supplements. After the age of 2 years, growth trajectory has continued along the 75th percentile for both height and weight. Laboratory tests were repeated at ages 2 years and 10 months (aspartate aminotransferase 47 IU/L, normal < 38 IU/L; alanine transferase 20 IU/L, normal < 40 IU/L; serum creatine kinase level 105 IU/L, normal < 194 IU/L), 4 years old (aspartate aminotransferase 36 IU/L; alanine transferase 19 IU/L; serum creatine kinase level 169 IU/L), and 6 years old (aspartate aminotransferase 36 IU/L; alanine transferase 21 IU/L; alanine to lysine ratio 1.58, normal < 1.5 to 2.5). During an acute illness owing to C difficile, the aspartate aminotransferase was on one occasion elevated to 50 IU/L; however, the serum creatine kinase level remained normal at 169 IU/L. Urine organic acids and serum amino acids have been normal at ages 3 and 6 years. Childhood Autism Rating Scale scores since beginning kindergarten have been under 30.