‘All that waddles is not dystrophy’

In the era of genetics, in patients with muscle disorders, genetic analysis has been replaced as the first-line tool of investigation. The authors emphasise the importance of history taking and clinical examination in a girl presenting with progressive limb-girdle pattern of weakness whose clinical exome sequence was negative, and also highlight the warning signs to look for a novel imitator of muscular dystrophy. A 12-year-old girl, first born of third-degree consanguineous parentage, had presented with progressive difficulty in walking, climbing upstairs and getting up from squatting posture from 11 years of age. She was evaluated at a regional hospital, as a case of limb-girdle muscular dystrophy with normal creatinine-phoshokinase, nerve conduction, echocardiography and negative clinical exome sequencing. Hence, the child was referred to our institute for a muscle biopsy to characterise the disease process. On reviewing the history, her illness started at 10 years and 6 months of age with pain localised to thighs and both knee joints, initially on unaccustomed exertion at the start of dance classes; later it used to be present even while walking on plain ground and was relieved while taking rest. Six months later, she went on to develop a limb-girdle pattern of weakness. The child also used to get tired excessively on walking short distances. However, there was no diurnal or seasonal fluctuation, and ocular or facio-bulbar weakness. Clinically, possibility of a metabolic myopathy (glycogen storage disorders, fatty acid oxidation defects, mitochondrial myopathy due to respiratory chain defects) or an endocrine myopathy was considered. On examination, she was short-statured with a height of 133 cm (<3rd centile, CDC); the weight of 20 kg (<3rd centile, CDC); and blood pressure of 130/80 mmHg (>90th centile). On muscle examination, there was evidence of proximal weakness (lower-limb predominant) with no selectivity in distribution, positive hip-up and Gowers' sign and exaggerated muscle stretch reflexes. There was no evidence of muscle hypertrophy/atrophy, tongue fasciculations, fatiguability and myotonia. During the hospital stay, while blood samples were collected for investigations with the help of tourniquet, she developed carpopedal spasm. Additional examination findings of short stature, hypertension and carpopedal spasm clinched the clue towards an ongoing chronic process and a probable hypocalcemic myopathy and the child was evaluated further. Her calcium profile was markedly deranged with total serum-calcium of 6.6 mg/dL (8.3–10.6 mg/dL), albumin 4.98 g/dL (3.5–5.2 g/dL), adjusted calcium 5.8 mg/dL (8.3–10.6 mg/dL), alkaline phosphatase 854 U/L (<500 U/L), magnesium of 1.4 mg/dL (1.3–2.7 mg/dL), 25-hydroxy-vitamin-D 14.6 ng/mL and parathyroid hormone level 1556.7 pg/mL (18.5–88.0 pg/mL). Her renal functions were deranged with serum urea of 79.18 mg/dL (10–44 mg/dL), creatinine 2.84 mg/dL (0.57–1.11 mg/dL) and ultrasound of the kidneys showed grade III medical renal disease with multiple small renal cysts suggesting renal-osteodystrophy as the probable pathomechanism for clinical manifestations. X-ray pelvis and skull showed features of osteosclerosis and osteopenia (Fig. 1). This child was supplemented with calcium, vitamin-D and was referred back to a nephrologist at the regional hospital for further management. The warning signs, which would have given clue in the index child includes: (i) exertion-related cramps with muscle and bone pain at onset; (ii) excessive fatigue without fatiguability suggesting a non-neuromuscular junction disorder; (iii) absence of selectivity suggesting a metabolic or an endocrine myopathy; (iv) exaggerated muscle stretch reflexes unlike an inherited muscle disease; and (v) absence of pseudohypertrophy, tendon contractures and a normal creatinine phosphokinase suggesting a non-dystrophic process. Myopathy secondary to hyperparathyroidism was first described by Vicale in 1949 as a progressive proximal weakness, associated with easy fatiguability, atrophy and exaggerated muscle stretch reflexes.1 Other manifestations described include lower limb predominant weakness, tongue fasciculations, glove and stocking distribution sensory loss of pain, impairment of vibration, hyperactive reflexes, ataxic tandem gait and poor memory.2-4 Exact pathophysiology remains uncertain. On investigations, creatinine kinase might be normal, electromyography would be non-specific and muscle biopsy might show group atrophy of type 2 muscle fibres suggestive of neurogenic features.5 To conclude, genetic analysis needs to be done only after detailed phenotypic characterisation keeping warning signs into consideration.