Acute intermittent porphyria presenting atypically as chronic, progressive, predominantly motor peripheral neuropathy of the lower limbs; a case report.

Int. Med J Vol. 6 No 2 December 2007

Acute intermittent porphyria presenting atypically as chronic, progressive, predominantly motor peripheral neuropathy of the lower limbs; a case report.

S.M.S. Azarisman¹ and A. A. Raymond ²

¹ Lecturer and Clinical Specialist, Department of Medicine, International Islamic University Malaysia, Jalan Hospital Campus, 25150 Kuantan, Pahang Darul Makmur.

² Deputy Dean (Graduate Studies), Senior Consultant Neurologist,Hospital Universiti Kebangsaan Malaysia,Jalan Tenteram, Bandar Tun Razak, 56000 Kuala Lumpur.

ABSTRACT

Peripheral, predominantly motor polyneuropathy is associated with a plethora of possible aetiologies and the investigative procedures to rule them out are extensive. A 31 year old lady presented with progressive lower limb weakness over a period of 2 years. Examination revealed symmetrical weakness (3⁺/5) of all distal muscle groups in the lower limbs with absent ankle jerk. There was no sensory loss. The nerve conduction study revealed a predominantly axonal motor neuropathy. Cerebrospinal fluid examination and other investigations to rule out potential causes of predominantly motor peripheral neuropathy were normal. The only positive findings were multiple qualitative assays for porphobilinogen in her urine.

INTRODUCTION

Acute intermittent porphyria (AIP) is an autosomal dominant inborn error of metabolism resulting from a partial deficiency of the third enzyme in the haem biosynthesis pathway¹. The clinical expression of the disease is usually ascribed to environmental factors such as certain drugs, infections, alcohol, fasting and stress. It typically presents acutely as a triad of abdominal pain, peripheral neuropathy and neuropsychiatric symptoms.¹ AIP is known as a great mimic and it can have many atypical manifestations. Hence the diagnosis of AIP is often based on biochemical tests rather than the clinical presentation.

We present a case of AIP presenting with chronic, progressive, predominantly motor peripheral neuropathy without any other ‘classical’ features. The progressive neuropathy developed over a period of two years resulting in severe debility and the diagnosis of AIP was delayed due to the pursuance of investigative measures to rule out other causes of peripheral neuropathy until she presented to us. We discuss the issues pertaining to its diagnosis and treatment in this patient.

Case Report

Mrs. MO was a 31 year old lady who complained of lower limb weakness which was slowly progressive over the last two years. The weakness began during the post-partum period following the delivery of her third child. The peri-partum period was uneventful and her child was developing normally. This weakness resulted in her inability to walk without a walking aid. Her husband also noted that she walked with a high-stepping gait and was unable to negotiate up staircases. She was however, able to get up from a squatting position and stand from a seated position. Her bladder and bowel functions were also normal.

Mrs. MO was a housewife and she denied any contact with industrial chemicals or effluent. She was previously healthy and led an active lifestyle. She did not indulge in illicit drug use and neither was she on any medications or supplements. She denied any symptoms suggestive of connective tissue diseases and as far as she knew no one in her immediate or extended family was beset with a similar problem. She did not suffer from any recent ailments nor has she had any recent vaccinations.

Clinical examination revealed marked reduction in power (3⁺/5), over all distal muscle groups in her lower limbs with absent ankle stretch reflexes. The proximal muscle groups were less affected with documented power of 4/5. All other reflexes were normal and her Babinsky sign was negative. Muscle bulk and tone was normal. All sensory modalities were normal. Upper limb and cranial nerve examinations were also normal. A nerve conduction study (NCS) revealed normal upper limb NCS bilaterally and absent common peroneal and tibial nerve compound muscle action potentials (CMAP) bilaterally with the impression that there was evidence of a predominantly axonal motor neuropathy of the lower limbs.

Her peripheral blood film and blood biochemistry were normal. Her serum B12, folate, cortisol, creatine kinase and thyroid function tests were also normal. Serological assays for anti-nuclear antibody, rheumatoid factor and anti-nuclear cytoplasmic antibodies were negative. Serum and urine electrophoresis were within normal limits and the magnetic resonance imaging of her spine was also normal. A lumbar puncture revealed no abnormalities in the cerebrospinal fluid. A qualitative assay of her urine was however, positive for porphobilinogen on three separate occasions. Twice whilst in hospital for acute exacerbations and once whilst on routine outpatient follow up in between acute exacerbations. However no urinary quantification of aminolaevulinic acid or porphobilinogen was carried out as the test was not available in-hospital and had to be sent out to an independent biochemical laboratory which entailed costs which she was unwilling to bear.

DISCUSSION

‘Porphyria’ is derived from the Greek word ‘porphuros’, which means red or purple.¹ The porphyrias are rare metabolic disorders caused by reduced activity of any of the enzymes in the haem biosynthetic pathway. Porphyrin precursors, overproduced in response to synthetic pathway blockages, accumulate in the body. They have been attributed to cause diverse pathologic changes, and become the basis for diagnostic tests.¹

Abdominal pain, peripheral neuropathy, and changes in mental status are the classic manifestations of an acute attack.¹ A clinical presentation without abdominal pain is unusual in acute porphyria, which may lead clinicians to entertain other diagnoses. It is best to make a careful, individualized assessment because atypical presentations do occur as exemplified in this case report. Other reported clinical manifestations of acute porphyria include neuropsychiatric symptoms and clinical signs, autonomic instability, dehydration, electrolyte imbalance and dermatologic features.^{1, 2}

None of the aforementioned clinical findings were found in this patient. The only positive finding is that of a progressive, predominantly motor peripheral neuropathy in the lower limbs, which developed over a period of 2 years. The nerve conduction study revealed a predominantly axonal motor neuropathy with absence of common peroneal nerve compound muscle action potentials (CMAP) and F waves bilaterally.

The peripheral neuropathy associated with acute porphyria tends to be progressive and involves predominantly the motor nerves, and is of axonal type on NCS.^{1, 2, 3, 4} This usually occurs over a period of several weeks and may take months to resolve.⁶ Muscular weakness can progress to quadriparesis, respiratory paralysis and arrest, which may resemble GBS.^{1, 6} One important discriminating factor is the absence of albumino-cytologic dissociation or increased protein with normal cellularity of the cerebrospinal fluid (CSF), a feature characteristic of GBS.⁶ This patient’s CSF findings were normal. Other factors against the diagnosis of GBS and CIDP, apart from the axonal picture on the NCS, are the prolonged course of the progressive neuropathy and the presence of porphyrin precursors in the urine.^{1, 2, 6}

Other causes of motor predominant peripheral neuropathy that need to be ruled out include heavy metal poisoning such as lead, organophosphate poisoning, infections such as poliomyelitis, botulism and west nile virus and myopathies (toxic and critical illness myopathy).⁶ Her history did not reveal any prior contacts with heavy metals or organophosphates and the bilateral, symmetrical distribution of her peripheral neuropathy goes against the diagnosis of poliomyelitis. The chronic unremitting course of the disease also rules out infection and connective tissue disease as the underlying aetiologic factor. This is supported by the negative serological assays for both groups in this patient.

The mainstay of treatment in porphyria is to reduce the synthesis of aminolaevulinic acid, resulting in a clinical and biochemical remission.² Treatment can either be preventive or supportive. Preventive treatment involves the adoption of a high calorie diet and avoidance of precipitants, mainly drugs such as sulphonamides and barbiturates.⁵ Supportive treatment involves the administration of intravenous glucose and haem arginate during acute attacks. Haem arginate or hematin suppresses aminolaevulinic acid synthase, the rate-limiting enzyme in the haem biosynthetic pathway, with a resultant decline in porphyrin production and marked symptom improvement.¹

In cases of AIP presenting with neuropathy, hematin needs to be administered early in the course of the disease, before irreversible neuronal damage has developed.⁴ This is because hematin cannot reverse an established neuropathy.² However case reports have shown interruption in the progression of the motor neuropathy with some improvement in motor function following the administration of hematin despite delays caused by the pursuance of alternate diagnostic modalities.⁴In her case she was advised to see a dietitian to promote a high calorie diet, supportive strengthening and ambulatory physiotherapy and avoidance of known precipitants. On follow up she was found to have improved slightly with improvement of her power to 4/5 in her distal lower limb muscle groups. Her ankle stretch reflexes however, remained absent.

CONCLUSION

Acute intermittent pophyria is a great imitator and may present as chronic, progressive, predominantly motor, peripheral neuropathy. An extensive investigative workup needs to be done in order to rule out other aetiologic possibilities. A high degree of awareness is also needed to initiate the appropriate investigations available for the porphyrias as its mimicry may lead clinicians astray. Once a diagnosis has been established, the initiation of treatment with intravenous glucose followed by haem arginate needs to be instituted early in order to halt further progression of the neuropathy which is irreversible. A number of case reports have shown some improvement in the motor neuropathy of patients with AIP. Treatment should be offered regardless of the temporal delay between diagnosis and initiating treatment.

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Correspondence;

Assistant Professor Dr. Azarisman Shah Mohd Shah

International Islamic University Malaysia,

Department of Medicine, Jalan Hospital Campus,

25150 Kuantan, Pahang, MALAYSIA

Ph: (O) 09-5132797 ext 3449

(h/p) 016-2096984

E-mail – risman1973@hotmail.com