Which clinical history findings are characteristic of autosomal-recessive limb-girdle muscular dystrophy 2I (LGMD2I)?

Updated: Aug 15, 2019
  • Author: Monica Saini, MD, MBBS, MRCP(UK); Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Answer

LGMD2I (fukutin-related proteinopathy; LGMDR9 FKRP; 19q13)

  • LGMD2I may be a fairly common cause of autosomal recessive LGMD, causing 11% of all cases in Brazil and 38% of cases in Denmark.

  • The disease is allelic with congenital muscular dystrophy 1C (MDC 1C). (See Congenital Muscular Dystrophy.)

  • The presentation of patients with a mutation in fukutin-related protein (FKRP) gene can vary from severe congenital muscular dystrophy to mild, late-onset LGMD.

  • The LGMD phenotype is variable. Patients can have a severe Duchenne-like presentation with delay in motor milestones, hypotonia, and severe proximal weakness. Progression to wheelchair by the teenage years and restrictive respiratory failure (even when patients are ambulant) is common. Like in Duchenne muscular dystrophy, treatment with corticosteroids may improve strength. The most common presentation is with a Becker-like onset with normal early motor milestones. An adult-onset form occurs at 11–40 years of age and is slowly progressive.

  • While cognitive impairment is universal in patients with congenital muscular dystrophy due to mutations in FKRP, it is absent or only mild in patients with LGMD2I. Neuropsychological testing shows mild impairment in executive functions and visuospatial planning, without substantial impairment in global and logic IQ, suggesting involvement of frontal and posterior parietal lobes. MRI abnormalities are heterogenous and, when present, always mild, varying from normal-to-mild white matter abnormalities, ventriculomegaly, cerebellar atrophy, and enlarged subarachnoid space. No structural brain abnormalities are noted. There is no correlation between MRI findings and cognitive abnormalities or mutation type. [20]

  • In a large study in Denmark, 2 groups of patients could be delineated based on genotype-phenotype correlations. Of the 38 patients studied, 27 (71%) had a homozygous mutation (826C>A), while 11 (29%) had a compound heterozygous mutation. [21]

    • The patients with a homozygous mutation had a later onset (mean of 18 y) and slower progression than patients with a compound heterozygous mutation. Only 15% lost the ability to ambulate by their mid 40s. Presentation with exertional myoglobinuria, calf hypertrophy and cardiomyopathy were all more common than in patients with a compound heterozygous mutation.

    • The patients with a compound heterozygous mutation had an earlier onset (mean of 5 y) and more rapid progression. All lost the ability to ambulate by their mid 20s. Tongue hypertrophy, more severe respiratory failure, contractures, and spine abnormalities were more common than in patients with a homozygous mutation.

  • Another large series from Norway found 88 patients (of 326) from 69 families with a mutation in FKRP (prevalence of ≥1 case in 54,000). [22] Seventy-six of these patients were homozygous for the 826C>A mutation, with a generally milder phenotype and a significantly later onset (age 14 y) than the patients with a heterozygous mutation (age 6.1 y). Other common features included difficulty with walking, running, or climbing as the presenting complaint and progression to involve arm weakness. About 20% used a wheelchair and 20% needed ventilatory support at the time of evaluation, about 25 years after onset.

  • Myoglobinuria (27%) and myalgia or cramps (60%) are common, [23] as can be isolated hyperCKemia. [24]

  • Cardiac involvement can occur in up to 60% of patients with LGMD2I as measured by reduced left ventricular ejection fraction. [25] There is no clear correlation between severity of cardiac disease and severity of muscle disease. Severely abnormal ejection fraction can occur in about 10% of patients and may cause symptomatic congestive heart failure. Rhythm abnormalities are not present.


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