Comparative Neuromuscular Laboratory

NEUROMUSCULAR CASE OF THE MONTH - NOVEMBER 2000

Failure to Grow, Limb Deformity and Weakness in an 8-9 Month Old Female Mix Breed
Contributed by Drs. Kerry Fisher, Alathea Fortner and Russ Howard
Animal Pain Management Center
Spokane, Washington

Clinical History
Kimba was acquired from an animal shelter at approximately 2 months of age. Since that time lethargy, poor growth and weakness to the point of collapse had been noted. Bradycardia was noted on physical exam along with abnormal genitalia and an umbilical hernia. Pituitary dwarfism was suspected. While laboratory work did not support hypothyrodism, an ACTH stimulation (Pre: 2.1 ug/dl, reference 0.0-10.0; Post: 4.2 ug/dl, reference 8.0-22.0) supported hypoadrenocorticism. The dog was initially treated with prednisone (1.25 mg q 12 hrs) and at a later date fludrocortisone was added (0.1 mg q 24 hrs). During this time Kimba's condition improved but weakness remained. Spinal and muscle pain were also reported. At the age of approximately 6 months she was referred to a veterinary teaching hospital. Body weight at this time was 28 pounds.

Physical and Neurological Examination
Kimba was bright and alert but quiet. Heart rate ranged from 40-60 beats/min. A pendulous abdomen was present with a 1-2 cm umbilical hernia. The genitalia were abnormally positioned on the ventral abdomen. Generalized muscle atrophy and a stiff-stilted gait were observed. The dog could not lift the head and look up. A valgus deformity (toes turned out) was present in the hind limbs. (See Video Clip). A decreased range of motion and pain on flexion and extension were found on palpation of the hock and elbow joints. A decreased ability to open the jaw was found. Pain was elicited over the cervical and lumbar vertebrae. No specific neurological abnormalities were noted.

Diagnostic Testing
CBC, serum chemistry panel including CK, urinalysis: No abnormalities

ECG: Bradycardia, no other electrical abnormalities

Thyroid Panel: No abnormalities

Endogenous ACTH: ACTH decreased 1.7 pmol/l (reference 6.7-25 pmol/l)

Spinal radiographs: Suspected retardation or malformation of osseous development

Electromyography: No abnormalities

Muscle biopsy: Type 2 fiber atrophy consistent with an endocrine associated disorder or chronic corticosteroid therapy

Assessment
Since an underlying systemic metabolic or endocrine disorder was suspected, the presence of inborn metabolic errors was investigated by quantitative evaluation of urinary organic acids, plasma amino acids, and plasma, urine and muscle carnitine. Urinary organic acid abnormalities included marked lactic (2929 mmol/mole creatinine; reference 0-197) and pyruvic (175 mmol/mole creatinine; reference 0-22) aciduria with moderate elevations of short chain fatty acids and ketones. Plasma alanine concentration was also markedly elevated (1037 UMOL/L; reference 210-661). There was urinary loss of carnitine esters (ratio ester/free 6.05; reference 0.0-3.0) and low muscle carnitine concentration (Free carnitine 1.80 nmol/mg protein; reference 7.20-18.0). A mitochondrial disorder associated with a blockage in oxidative metabolism at the level of pyruvate was suspected based on the pattern of organic and amino acid abnormalities (Fig. 1). Pyruvate is shuttled to either lactate or alanine when oxidative decarboxylation is blocked resulting in increased excretion of lactate and pyruvate on urinary organic acid analysis and elevated alanine on plasma amino acid analysis.

Figure 1.

Therapeutic Rationale
Treatment for Addison's disease was continued as previous. Based on the results of organic and amino acid analysis and carnitine quantifications, a therapeutic trial of L-carnitine (50 mg/kg BID), coenzyme Q10 (100 mg SID), and riboflavin (100 mg SID) was initiated. Carnitine combines with abnormal organic acids to form carnitine esters that are excreted in the urine. Urinary loss of carnitine may result in depletion of muscle carnitine. Since lactic and pyruvic aciduria are commonly associated with a mitochondrial disease, supplementation with cofactors for electron transport and free radical scavengers are indicated. Mitochondrial diseases may have a broad spectrum of presentations and involve multiple organ systems. Further investigations would be necessary in this dog for evaluation of suspected mitochondrial disease. Following 6 weeks of the above therapy, a dramatic increase in muscle strength and activity was reported. The dog could lift the head and look around. The pendulous abdomen had resolved.