INTERLACE OF TWO RARE INHERITED DISEASE CAUSING MUSCLE ATROPHY: ACUTE INTERMITTENT PORPHYRIA AND SPINAL MUSCULAR ATROPHY
Here, we present a phenomenal case of a 27-year-old man who harbors mutations in both HMBS and SMN1 genes.
Introduction
Porphyrias are a group of metabolic diseases due to mutations causing different enzyme defects and resulting in the accumulation of metabolic intermediates causing gastrointestinal, skin, and neurological manifestations [1]. Acute intermittent porphyria (AIP) is the most commonly encountered form of hepatic porphyria. Heterozygote patients may experience acute attacks when exacerbating factors are introduced, despite most remaining symptom-free [2]. Spinal muscular atrophy (SMA) is an autosomal recessively inherited disease that occurs as a result of degeneration inlower motor neurons. SMN1 gene deletions constitute most of the cases whereas mutations in SMN2 gene is not known to cause spinal muscle atrophy [3]. Type 3 SMA is a milder form of the disease with childhood or adolescent onset; thus milder limitations than SMA1 or SMA2 are observed in gait of patients [4].
CASE REPORT
Our patient attended the paediatrics department with sudden falls and a tendency to tiptoe-walk starting at the age of 4. He is a 4 pack-year smoker and does not consume alcohol at present. He has no known prescribed medications. He has no other known comorbid diseases and has not undergone any procedures.
He was born term, vaginally, and has completed all developmental milestones on time with his peers. His independent walking age was 11 months. He complaints of fatigue and weakness in all extremities predominantly on the lower extremities. Initially diagnosed at the age of 4 with myopathy, diagnosis of SMA was only possible after having EMG at age 5 which showed slowly progressive anterior horn disease. Homozygous deletion in the exons 7-8 of SMN1 gene, with 4 copies of SMN2 confirmed the SMA type 3 diagnosis. At age 27 he still is ambulatory but with difficulty and limited walking distance but has a full-time home-based profession. Although he does not need a wheelchair for daily chores, he usually does needs it for long distances. In the last year, his weakness worsened even more, especially prominent on his left side. On his final neurological examination cranial area and neck muscles were normal, axial muscles were moderately weak, muscle strength in extremities were around 4/5 medical research council (MRC) in the upper and 2-3/5 MRC in the lower proximal muscles. Bilateral but more prominent left, Achilles contracture was observed. The right calf was hypertrophic. Deep tendon reflexes were absent. Superficial and deep sensory examinations were normal. His family history is negative for parental consanguinity or SMA but consists of three cousins suffering from AIP. Our patient’s genetic result revealed a heterozygous mutation in HMBS gene, c913.2A>G (IVS13-2A>G) suggesting AIP. Similarly, his mother who migrated from the Balkans also had heterozygous mutations in HMBS, hemochromatosis (HFE), and 5-aminolevulinate synthase 2 (ALAS-2) genes. Both family members tested negative for urine porphobilinogen. Upon questioning, our patient did not claim any porphyria suggesting symptoms such as constipation, abdominal pain, skin lesions, and abnormal urine color.
DISCUSSION
AIP is a rare disease with a prevalence of 1 to 8 per 100.000 in European countries. Our patient did not present with any porphyria-like symptoms so far which might be related to his heterozygous mutation [6]. Porphyria-suggesting laboratory results such as urine porphobilinogen, ALAS-1, and urine protoporphyrin were negative. However, we cannot rule out the possibility of an attack in the future.
Both diseases have challenges starting from the diagnosis. Porphyria presents with nonspecific symptoms making differential diagnosis more challenging although it can easily be diagnosed by urine porphobilinogen.
The diagnosis of SMA, especially SMA 3, is also may be challenging as the clinical picture is very similar to a limb girdle type myopathy and elevated CK levels. Therefore, children with gait problems often bring dystrophy to mind initially [7]. Similarly, in our patient SMA diagnosis was made 2 years after the myopathy diagnosis and genetic analysis for porphyria was only requested owing to the family history.
It is known that SMA is a progressive disease affecting predominantly proximal muscles [8]. In the neurological examination performed, predominant proximal weakness and atrophy were detected in our patient. Proximal muscular atrophy had also been reported in several cases of porphyria without any aberrant symptoms such as abdominal pain, mainly due to neurovisceral neuropathy [9]. Porphyria education is a fundamental element to overcome this enigma. Necessary awareness seminars amongst physicians and patients must be conducted.
Although there were no porphyria-like attacks in our case, knowing beforehand that there is a disease that can be exacerbated by triggering factors such as smoking might facilitate the diagnostic process in the future if there are complaints and can prevent complications.
To our knowledge, this is the first case ever reported of an individual possessing mutations for both SMA and porphyria. Further gene analyses are needed in patients that are known to suffer from a congenitally inherited disease to uncover a possible secondary diseases.
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