A rare dual diagnosis of Alport syndrome and Charcot-Marie-Tooth disease

INTRODUCTION

Alport syndrome is one of the rare genetic disorders affecting around 1 in 50,000 individuals. Main features include progressive microscopic hematuria and proteinuria, which can progress to chronic kidney disease, associated with extrarenal complications, including sensorineural hearing loss and ocular abnormalities (anterior lenticonus, retinal flecks).^[1] Alport syndrome is inherited through various patterns, including X-linked (most common), autosomal recessive, autosomal dominant, and digenic inheritance patterns. Alport syndrome results from mutations in COL4A3, COL4A4, and COL4A5 genes that lead to disruption in the formation of the α3-α4-α5 chain in the collagen IV network of the basement membrane.^[2] Diagnosis depends on urine analysis, histologic examination, and genetic testing, with advancements in next-generation sequencing aiding identification. Although no specific treatment exists, early diagnosis improves outcomes, emphasizing the importance of genetic testing for prognosis and familial screening.

Charcot–Marie–Tooth (CMT) disease is the most prevalent inherited peripheral neuropathy.^[3] Manifested by gradually increasing motor and sensory nerve dysfunction associated with significant atrophy of the calf muscle, diminished ankle dorsiflexion strength, depressed tendon reflexes, and pes cavus. CMT is caused by one of several pathogenic variants in genes whose protein products are expressed in myelin, gap junctions, and/or axonal structures within peripheral nerves. CMT has significant genetic and clinical heterogeneity.^[4,5] At present, over 80 genes have been implicated in various CMT subtypes.^[6] Although CMT can occur at any age, it predominantly arises between the first and third decades, severely impairing patients’ social participation and life quality from an early stage.^[6,7] Therefore, elucidating the genetic etiology of CMT is critical for precision diagnosis, classification of subtypes, timely intervention, and genetic counseling for subsequent generations.

CASE REPORT

Male patient, 21 years old, was born and is living in Oman, a student, has no special habits of medical importance. History of present illness: The condition began at the age of 6 years, when the patient developed persistent hematuria. The patient sought medical advice, and investigations revealed hematuria, proteinuria, no skin rash, no arthritis, and no history of upper respiratory tract infection. Routine investigations were conducted and revealed persistent proteinuria and hematuria. The immune profile was negative, including (ANA/AntiDNA Ab/ANCA P and ANCA C) as illustrated in Supplementary Table 1. Complement C3 and C4 were normal, and virology (HBVAb/HCV Ab/HIV Ab) were all negative. Renal function tests were normal [Supplementary Table 1]. His abdominal ultrasound revealed normal-sized kidneys with normal echotexture and no family history of renal disease. There was associated severe bilateral SNHL and visual disturbance. Renal biopsy was done as illustrated in Figure 1; Light microscopy: Glomeruli showed a mild focal and segmental increase in mesangial cells and matrix; there was no end capillary hypercellularity, no fibrinoid necrosis, or crescent. Immune fluorescence: There was granular capillary wall staining for IgM+, other immune globulins, and complement was negative. Electron microscopy: 10 glomeruli examined, glomerular BM is of variable thickness and has irregular outer contours. In places where the membranes are thinner, the thickness measures between 170 and 250 nm in both the thin areas and where the membranes appear thicker. There is splitting and multilamination of the lamina densa; epithelial foot processes are generally preserved with patchy effacement, mesangial areas show a mild increase in matrix, and no electron-dense deposit is seen—conclusion: feature of native kidney biopsy suggestive of hereditary nephropathy of Alport type. Genetic testing confirmed autosomal recessive Alport syndrome (homozygous mutation in COL4A4 exon 17). Electroretinography: Moderate rod and cone dysfunction that is non-specific but can be seen in pigmentary retinopathy and in patients with Alport disease and early retinitis pigmentosa. Other issues not related to Alport syndrome: The patient had microcephaly, learning difficulties, and poor school performance. Family history: His uncle was suffering from progressive muscle weakness till the end of his life, and was bedridden. His uncle had microcephaly, learning difficulties, and died at the age of 37 years. Social history: While a student, he had poor performance, had two healthy siblings, and his parents are second-degree relatives. Regular medications: Lisinopril 7.5 mg, riboflavin 100 mg bid for migraine (as prescribed by pediatric neurologist). At the age of 19 years old, the patient suffered from progressive weakness that progressively worsened along with continuous pain, which increased with exhaustion. He asked for medical advice at multiple institutes for the pain. CPK reported high >800, and echocardiography was done to rule out cardiomyopathy. Neurological evaluation revealed a generalized decrease in muscle bulk, more pronounced in the upper limb compared to the lower limb. Weakness was mainly proximal, more pronounced than distal. Sensation was intact, with no fasciculation, and there was a generalized decrease in muscle bulk. While in the lower limb, there was bilateral tenderness in both thighs and legs, associated with weakness in the proximal hip. Knee flexion was grade 3, while hip and knee abduction, dorsiflexion, and plantar flexion were grade 4. Sensation was intact, and there was no fasciculation. Reflexes were diminished, with plantar withdrawal and inability to perform tandem gait. Nerve conduction was performed, revealing absent sensory nerve action potentials from the bilateral sural and superficial peroneal. Bilateral median sensory nerve conduction showed delayed peak latency, normal amplitude, and conduction velocity. The rest of the motor and F wave conduction parameters are within normal, bilateral median/ulnar/ peroneal/tibial, except the right peroneal nerve, which had delayed distal latency with normal amplitude and conduction velocity. The bilateral ulnar sensory conduction study was normal.

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Figure 1:

Renal biopsy. (a) Lower power image of the glomerular ultrastructure showing global thinning of glomerular basement membranes. Podocyte foot processes are preserved (4000x), (b) Glomerular basement membranes are thin measuring less than 200 nm (30000x), (c) There is thinning and splitting of the lamina dense, red arrows (15000x), (d) Glomerular basement membrane showing typical basket-weave appearance with lucent areas containing small electron dense granules ‘breadcrumbs’, red arrow (25000x).

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DISCUSSION

A combined association between Alport and CMT syndrome is considered a rare syndromic overlap reported in the medical literature. Some patients present with renal disease in the form of hematuria and proteinuria that progress to ESRD (end stage renal disease), and associated peripheral neuropathy (CMT-like features), hearing loss (from both conditions). The overlap is usually due to contiguous gene deletions or mutations in COL4A5 (Alport syndrome) and neighboring genes that affect neuropathy. Hence, we built our diagnosis depending on history and clinical examination, including microscopic hematuria from childhood, progressive sensorineural hearing loss, and peripheral neuropathy symptoms (distal weakness, foot drop, and pes cavus). Urine analysis: Hematuria and proteinuria. Audiometry: sensorineural hearing loss. Eye examination: Anterior lenticonus, retinal flecks. Nerve conduction studies/EMG: Demyelinating or axonal neuropathy (CMT-like). Renal biopsy: Irregular thickening and lamellation of the glomerular basement membrane. Genetic testing (gold standard) COL4A5 mutations (Alport). A homozygous likely pathogenic variant was identified in the SBF1 gene. The result is consistent with a genetic diagnosis of autosomal recessive CMT disease type 4B3. There is no definitive cure, and treatment is supportive, aiming to delay kidney failure and improve quality of life. Including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors can be used to control proteinuria to delay the development of ESRD, and dialysis for ESRD or kidney transplantation. As regards CMT: Physiotherapy, Orthoses, Ankle Foot Orthosis for foot drop. Orthopedic surgery for severe foot deformity. Hearing aids or a cochlear implant. Eye monitoring and correction for lenticonus and retinal changes. Genetic counseling is essential for affected families (X-linked inheritance). Prognosis for Alport syndrome, males (X-linked): usually progress to ESRD by age 20-30, while females: milder course but risk of late kidney disease. CMT does not shorten life expectancy but causes progressive motor disability. Prognosis depends mainly on the progression of renal disease and the availability of a transplant. Neuropathy and hearing loss reduce quality of life but can be managed with supportive care. In the literature, there are no typical cases of AS and CMT. Still, there is a renal association with CMT, as seen by Anandh et al. (2018)^[8] 150, who found associated membranous nephropathy in a patient with CMT disease. They discovered that heterozygous mutations in the myelin protein (MPZ) in humans are detected in CMT disease type Ib. They speculate that the presence of MPZ mutations in this patient is responsible for both the renal and neurological clinical manifestations.^[9]

CONCLUSION

Chronic polyneuropathy, predominantly sensory, could be part of hereditary polyneuropathy (CMT), warranting further evaluation. Genetic studies revealed autosomal recessive Alport syndrome, CMT disease, muscular dystrophies, and TANGO2 mutations. Targeted gene request: TANGO2. Homozygous pathogenic variants were identified in the COL4A4 gene. The genetic diagnosis of autosomal recessive Alport syndrome type 2 is confirmed. A homozygous likely pathogenic variant was identified in the SBF1 gene, the result consistent with a genetic diagnosis of autosomal recessive CMT disease type 4B3.