Article Text

PDF

An unusual phenotype of McLeod syndrome with late onset axonal neuropathy
  1. M Wada1,
  2. M Kimura1,
  3. M Daimon1,
  4. K Kurita1,
  5. T Kato1,
  6. Y Johmura2,
  7. K Johkura2,
  8. Y Kuroiwa2,
  9. G Sobue3
  1. 1Third Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan
  2. 2Department of Neurology, Yokohama City University School of Medicine, Yokohama, Japan
  3. 3Department of Neurology, Nagoya University School of Medicine, Nagoya, Japan
  1. Correspondence to:
 Dr Manabu Wada
 Third Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan; mwadayacht.ocn.ne.jp

Statistics from Altmetric.com

McLeod syndrome is a rare multisystem disorder defined by weak expression of the Kell glycoprotein antigens and the absence of a red blood cell surface antigen, Kx.1,2 The gene responsible for McLeod syndrome, XK, was cloned in 1994.1 The XK protein contains the Kx antigen missing in patients with McLeod syndrome. Mutation analysis of the XK gene has shown different deletions or point mutations in families with this condition.2,3

Clinical features of McLeod syndrome are reported to be heterogeneous.2,4,5 Clinical manifestations include acanthocytosis, an increased level of serum creatine kinase (CK), progressive muscular atrophy, seizures, and involuntary movement. As the symptoms and signs of this syndrome seem to be variable even among siblings, it is sometimes difficult to distinguish the condition from other neuromuscular disorders by clinical features and conventional examination.

We report here two cases of McLeod syndrome in brothers and emphasise the variable features of the disease. Phenotypic variability was obvious in the two patients, and one case was unusual because the clinical features greatly resembled an axonal form of Charcot-Marie-Tooth disease.

Case reports

Case 1

A 50 year old man had been complaining of weakness and paraesthesiae in both legs. He first noted weakness in the right leg at the age of 37. Subsequently, the symptom extended to both legs, and he began to be unsteady on his feet. At age 47, he noticed muscular atrophy in his legs. There was no consanguinity in the family. A neurological examination in August 2000 revealed sensorimotor neuropathy with severe weakness and atrophy in both calves and shins (fig 1A). Deep tendon reflexes were diminished in the lower limbs. The ability to sense pinprick and light touch was mildly impaired in the distal parts of the lower extremities. Vibration sense was impaired in both feet. Abnormal involuntary movement was not seen.

Figure 1

(A) Marked amyotrophy of both legs in case 1. (B) Sural nerve specimen obtained from case 1 showing moderate loss of myelinated fibres. Onion bulb formation is not observed. Toluidine blue stained transverse semithin section. Bar=50 μ. (C) Axial T2 weighted magnetic resonance image of case 2, showing atrophy of the heads of the caudate nuclei. (D) Muscle biopsy specimen obtained from the left biceps brachii of case 2. The specimen shows increased variability of fibre diameter, and a group of basophilic fibres. Bar=100 μ. (E) Direct DNA sequencing of the XK gene. A five base deletion in exon 3 is present at nt position 938 to 942 from the 5′ end of the cDNA.

Laboratory investigations were unremarkable except for a raised serum CK concentration (1510 IU/l, normal <255). Serum levels of thyroid hormones, vitamin B-12, vitamin E, antinuclear antibody, anti-DNA antibody, and anti-SS-A/SS-B antibodies were normal. In nerve conduction studies, neither compound motor action potentials (CMAP) nor sensory nerve action potentials (SNAP) were elicited in the patient’s lower extremities.

Histopathological features of a sural nerve biopsy specimen showed moderate myelinated fibre loss and abundant axonal sprouting in residual myelinated fibres (fig 1B), while onion bulb formation was absent. No apparent amyloid deposits or inflammatory cell infiltrates were seen in the epineurial and endoneurial tissues. An axonal form of Charcot-Marie-Tooth disease was strongly suspected from the clinical features and pathological findings. Although mutation analysis available for the peripheral myelin protein zero and connexin-32 was done, no mutation was detectable in these genes.

Case 2

A 62 year old man, an elder brother of case 1, was admitted for evaluation of a progressive movement disorder in December 2001. On neurological examination, he had choreic involuntary movement of the extremities, mild weakness in the thighs, and hyporeflexia in all limbs. Pathological reflexes were not elicited, and he showed no sensory disturbance. No personality change or cognitive impairment was seen.

A peripheral blood smear showed acanthocytes in 4% of the red blood cells by May-Giemsa staining. Serum CK was raised to 1710 U/l, with predominant MM isozyme. Brain magnetic resonance imaging showed mild atrophy of the bilateral frontal lobes and caudate nuclei (fig 1C). Nerve conduction studies of the lower limbs suggested mild sensory neuropathy, showing reduced SNAP in the sural nerves (left 2.3 μV, right 3.6 μV).

A muscle biopsy specimen taken from the left biceps brachii showed increased variability in fibre diameter. The most striking findings were some scattered necrotic fibres, several basophilic fibres, and an increased number of central nuclei (fig 1D).

An evaluation of Kell antigen expression was subsequently undertaken. Expression of Kell antigens (K2, K4, and K7) on red blood cells was reduced, a result consistent with McLeod syndrome.

Molecular analysis

After informed consent had been obtained from the brothers, genomic DNA was extracted from peripheral blood by standard procedures. Exons of the XK gene were subsequently amplified by polymerase chain reaction as described by Ho et al.1 The analysis showed a five base deletion in exon 3 at nt positions 938 to 942 from the 5′ end of the cDNA. This mutation results in a frame shift at codon 286 and the premature stopping of translation at codon 301, as reported previously.2 This mutation was found in both cases 1 and 2, whose clinical phenotypes were extremely different.

After mutation analysis of the XK gene, we confirmed the presence of acanthocytes in a peripheral blood smear of case 1.

Comment

To date, the clinical features of McLeod syndrome have been reported to be heterogeneous.2,5 The clinical features and conventional pathological findings in this condition are sometimes difficult to distinguish from other neuromuscular disorders because the expression of symptoms and signs seems to be variable, even among siblings.2,5 In many cases, chorea, seizures, or muscular atrophy are the most frequently presented symptoms. Danek et al recently reported clinical features of 22 affected patients with mutation analysis of the XK gene.2 In their investigations, limb chorea—which reflects CNS involvement in McLeod syndrome—was described in all patients. It is extremely difficult to make a diagnosis of this disease where the symptoms and signs are restricted to the peripheral nervous system.

In the present investigation, case 2 was characterised clinically by choreic movement and mild muscular atrophy, frequently seen in the reported cases of McLeod syndrome. In contrast, the symptoms in case 1 were extremely rare. Case 1 showed late onset of symptoms, slowly progressive weakness and amyotrophy of the lower extremities, areflexia, glove and stocking type sensory impairment, an increased level of serum CK, and pathological features with axonal degeneration of the nerve biopsy specimen. He showed no apparent central nervous system involvement 14 years from onset.

Our case 1 was clinically and pathologically indistinguishable from an axonal form of Charcot-Marie-Tooth disease without McLeod serology.

McLeod syndrome should be considered in patients with axonal sensorimotor neuropathy and high CK activity. Abnormal red cell morphology may be a clue to the diagnosis.

References

View Abstract

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.