Diagnosis of adrenomyeloneuropathy (AMN) — the adult-onset form of adrenoleukodystrophy (ALD) — should be considered in men with symptoms suggestive of hereditary spastic paraplegia, such as weakness in the legs, a Chinese study advises.
The research, which showed that 4.9% of 142 Chinese people initially diagnosed with hereditary spastic paraplegia actually had AMN, also identified two new ABCD1 mutations, which is the underlying cause of ALD.
The study, “Spastic paraplegia as the predominant phenotype in a cohort of Chinese patients with adrenoleukodystrophy,” was published recently in the journal Molecular Genetics & Genomic Medicine.
ALD, a rare genetic disease that mainly affects men, is caused by mutations in the ABCD1 gene, leading to a deficient ALDP protein. This deficiency results in the toxic build-up of very-long-chain fatty acids (VLCFAs) in several tissues and organs, including the spinal cord, brain, and adrenal glands (the small hormone-producing glands located above the kidneys).
People with AMN, ALD’s adult-onset form, may start to develop a variety of symptoms in their 20s and 30s, including progressive stiffness and weakness of the legs, impaired muscle coordination, walking difficulties, sensory abnormalities, speech difficulties, adrenal insufficiency, sexual dysfunction, and bladder control issues.
If the disease affects the brain, in addition to the spinal cord, patients also may show behavioral abnormalities, hearing problems, vision loss, and/or seizures.
Hereditary spastic paraplegia is a group of inherited neurologic disorders mainly characterized by walking difficulties due to muscle weakness and muscle tightness in the legs. The similarities between symptoms of AMN and hereditary spastic paraplegia, as well as the absence of brain lesions in most AMN patients, increases the likelihood of misdiagnosis.
In agreement, a recent Chinese study reported the case of seven people who showed symptoms suggestive of hereditary spastic paraplegia, but who were diagnosed genetically with ALD. Only four of them had adrenal insufficiency.
Chinese researchers at Zhejiang University School of Medicine now identified seven people with AMN who were diagnosed initially with hereditary spastic paraplegia, two of them with new ABCD1 mutations.
The researchers analyzed the clinical and genetic data of 142 people diagnosed with hereditary spastic paraplegia at the Second Affiliated Hospital of Zhejiang University School of Medicine, in China.
Results showed that seven men (4.9%) had ALD-causing mutations in the ABCD1 gene, along with symptoms consistent with AMN.
Among the seven different ABCD1 mutations found in these patients, five were known to be disease-causative (c.346G>C, c.521A>G, c.829G>T, c.1415_1416delAG, and c.1849C>T) , while two were reported for the first time — c.454C>G, and c.1452_1482del. Further analysis indicated that both these new mutations were likely to cause ALD.
Interestingly, one of the previously known mutations — c.346G>C — was not detected in either parent of the affected patient, suggesting that it may have developed for the first time in this man, without being inherited from his parents.
In general, the seven men analyzed experienced the first disease symptoms at a mean age of 32 (ranging from 24 to 45 years), and they had lived with the disease for two to 11 years. Only one man had a history of ALD in the family.
The most common initial symptom was weakness in the legs. Of the six men who underwent an evaluation of the health of nerve cells controlling muscles, five showed abnormalities. Two men had urinary incontinence, and one of them also reported sexual dysfunction.
No patient showed cognitive impairment or obvious brain lesions, although one man had extensive atrophy (shrinkage) in the thoracic (upper back) region of the spinal cord.
All five men who underwent biochemical tests had higher-than-normal levels of VLCFA in the blood, and two of them showed signs of adrenal insufficiency.
Overall, the findings “expand the mutation spectrum of ABCD1, and indicate that ALD represent[s] a significant portion (4.9%, 7/142) of the spastic paraplegia entities,” the researchers wrote, adding that “genetic investigations and [blood] VLCFA test are critical for [ALD] diagnosis.”
The team emphasized that AMN diagnosis should be considered, in addition to hereditary spastic paraplegia, in patients with walking difficulties due to weakness in the legs.
Researchers also noted that since adult men with ADL are at risk of developing brain inflammation and damage, “long‐term follow‐up and regular MRI examination are necessary” in these patients.