Background:
Madras Motor Neuron Disease (MMND) is a rare variant of motor neuron disease that predominantly affects children and young adults. It is characterized by slowly progressive limb weakness, bulbar involvement, upper and lower motor neuron signs, and sensorineural hearing loss. Fewer than 200 cases have been reported worldwide.
Case Presentation:
We report a 13-year-old Pakistani girl born toconsanguineous parents who presented with a two-year history of progressive distal limb weakness and a four-year history of bilateral hearing loss. Eight months before presentation, she developed non-fatigable bilateral partial ptosis and dysphagia without diurnal variation. Neurological examination revealed tongue atrophy with fasciculations, depressed palatal movements, distal muscle wasting, minipolymyoclonus, pyramidal signs, and a high-steppage gait. Pure-tone audiometry demonstrated bilateral mild-to-moderate conductive hearing loss, an unusual finding in MMND, where sensorineural hearing loss is typically reported. Magnetic resonance imaging of the craniospinal axis was normal. Electrophysiological studies showed active denervation consistent with ananterior horn cell disorder.
Conclusion:
This case highlights an atypical presentation of MMND with bilateral conductive hearing loss and partial ptosis. Recognition of such uncommon manifestations may broaden the known clinical spectrum of MMND and facilitate earlier diagnosis of this rare disorder
1.Introduction
Madras Motor Neuron Diseasesis characterized clinically by younger age of onset,weakness and atrophy of the limbs muscles and multiple cranial nerve palsies particularly the seventh, ninth, twelfth, and sensorineural hearing loss with unique geographic distribution to the southern part of India [1], but was also reported from China [2], Korea [3], Turkey [4], Thailand [5] and northern areas of Pakistan.This case report will highlight a rare disease with divergent clinical features and help identify it or enable early diagnosis infuture studies.
2.Case Presentation
A young girl of 13 years of age, born of consanguineous parentage, presented in the outpatient department of neurology with the complaint of generalized weakness of all four limbs for the last 2 years. She reported bilateral hearing loss for the last four years. She had developed bilateral drooping of eyelids with swallowing difficulty for the last 8 months. She had a normal birth history. There was no history of preceding febrile illness or vaccination. She gave no history of seizures, lossof consciousness, or sensory disturbances and had intact sphincters. There was no family history of similar complaints. As per her complaint, her weakness was progressive initially but currently static and she is mobile without support. She had non-fatigable, non-progressive drooping of the eyelids and swallowing difficulty with no diurnal variation
On examination, she was of normal height and thin-built, conscious, and oriented with intact higher mental function. She had non-fatigable bilateral partial ptosis with nasal speech. Her pupils were equal bilaterallyand reactive to light with intact extraocular movements. She had bilateral conductivehearing loss. Fundoscopy examination was normal. Tongue fasciculations with atrophy were observed. Palatal movements were depressed bilaterally with a depressed gag reflex. Wasting oftheshort muscles of the hands and feet was present resulting in clawing ofthehands and hammering ofthetoes. Minipolymyoclonus was noted. The tone was increased in all limbs. Power in both upper and lower limbs was 5/5 proximally and 4/5 distally with intact deep tendon reflexes and upgoing plantars. Pin-prick and joint position sensations were intact. Extrapyramidal and cerebellar abnormalities were absent. She had a high-steppage gait. The rest of her systemic examinations were normal.
In her investigations, all routine blood investigations were normal; ANA, ENA and thyroid function profiles; creatine kinase; aldolase; vitamins D and B12; parathyroid hormone and ACE levels were within normal limits. HIV screening testing and Anti Acetylcholine receptor antibody (Anti Ach) were negative. CSF studies were not done due to lack of consent. Neuro-imaging was done includingMagnetic Resonance Imaging (MRI). TheCranio-spinal axis was normal. Her pure tone audiometry (PTA) showed bilateral mild to moderate conductivehearing loss. Her Nerve conduction study (NCS)/ EMG showed motor axonal polyneuropathy with active denervation suggestive ofanAnterior horn cell disorder.
There is no specific treatment for MMND. However, supportive and symptomatic therapy like hearing aids is advised. Patients with MMND usually have a normal lifespan. Pros/cons, risksand prognosisareexplained in detail.
3.Discussion
It is a very rareand unique entity with only 150 reported cases worldwide. MMND was described as a sporadic form of benign childhood motor neuron disease. However, several reports of familial MMND were described a few years later with an autosomal recessive form of inheritance.
Research suggests that Madras Motor Neuron Disease (MMND) may be linked to inflammation and environmental factors [6], based on autopsy findings and a positive response to intravenous immunoglobulin treatment in one case [2]. Additionally, abnormal citrate metabolism, characterized by low citrate levels, has been proposed as a potential contributing factor. However, further studies are necessary to confirm these findings and fully understand the underlying causes of MMND.
Several inherited childhood motor neuron disorders closely resemble Madras motor neuron disease (MMND) and should be considered in the differential diagnosis [7]. Brown–Vialetto–Van Laere (BVVL) syndrome shares the characteristic combination of progressive lower cranial nerve palsies, limb weakness, and sensorineural hearing loss; however, it is now recognized as a riboflavin transporter deficiency caused by mutations in SLC52A2 or SLC52A3 and is potentially treatable with high-dose riboflavin supplementation [8]. Fazio–Londe syndrome is regarded as part of the same disease spectrum as BVVL but typically lacks sensorineural hearing loss despite exhibiting progressive bulbar palsy and lower motor neuron involvement. Boltshauser syndrome also presents with progressive bulbar dysfunction and hearing impairment but is distinguished by isolated vocal cord paralysis and a more restricted pattern of cranial nerve involvement. Nathalie syndrome is differentiated by the presence of additional systemic manifestations, including hypogonadism, cataracts, cardiac conduction abnormalities, and deafness, features not seen in classical MMND [9]. In contrast, MMND predominantly presents with juvenile-onset limb weakness, multiple lower cranial nerve palsies, and sensorineural hearing loss, without riboflavin transporter gene mutations or the multisystem involvement characteristic of these syndromes, supporting its recognition as a distinct clinico-genetic entity.
The most distinctive feature of our patient was bilateral conductive hearing loss. Sensorineural hearing loss is considered a hallmark clinical feature of MMND and has beenconsistently reported acrossmost published cases. In contrast, pure-tone audiometry in our patient demonstrated bilateral conductive hearing loss, suggesting a broader phenotypic spectrum of the disease than previously recognized.
The first reported case from Pakistan, published in 2013, involved a 21-year-old male with bilateral sensorineural hearing loss, distal limb weakness, facial weakness, dysphagia, and respiratory involvement [10]. Our patient differed in several respects, including a younger age at presentation,bilateral partial ptosis, and conductive rather than sensorineural hearing loss. These differences highlight the clinical heterogeneity of MMND and emphasize the importance of considering this diagnosis even in patients with atypical auditory manifestations.
Although genetic testing was unavailable in our setting,the characteristic clinical and electrophysiological findings strongly supported the diagnosis of MMND after exclusion of relevant differential diagnoses.
4. Conclusion
Madras motor neuron disease (MMND) should be considered in young patients presenting with a combination of upper and lower motor neuron signs, bulbar dysfunction, and cranial nerve involvement. This case expands the recognized clinical spectrum of MMND by demonstrating bilateral conductive hearing loss rather than the classically described sensorineural hearing loss. Awareness of such atypical presentations may aid earlier diagnosis and improve recognition of this rare motor neuron disorder, particularly in resource-limited settings.
List of Abbreviations
NCS: Nerve Conduction Studies
MMND: Madras Motor Neuron Disorder
BVVL: Brown-Vialetto-Van Laere
AHCs: Anterior Horn Cell Disorders
5. Declarations
Ethical approval: Not required.
Consent to participate and publication: Consent to participate and publication has been obtained from the patients.
Competing interests: The authors declare that they have no competing interests.
Funding: None.
Availability of data and materials: Not applicable.
Authors’ contributions: All authors participated in data collection and manuscript writing. All authors read and approved the manuscript.
Acknowledgements: We are grateful to our co-author who contributed to this study.
AI Statement: The authors declare that generative AI (ChatGPT Plus) was used solely for language polishing. All scientific content, interpretation, and final approval of the manuscript were performed by the authors.
References
- Gourie-Devi M, Nalini A. Madras motor neuron disease variant, clinical features of seven patients. Journal of the Neurological Sciences. 2003 May 15;209(1-2):13-17.
- Fan D, Fu Y, Sun AP, Kang D. Madras pattern of motor neuron disease: improvement of symptoms with intravenous immunoglobulin. National Medical Journal of India. 2004 May 1;17(3):141-142.
- Im SH, Kim NH. First case of Madras motor neuron disease from Korea. Muscle & Nerve: Official Journal of the American Association of Electrodiagnostic Medicine. 2008 Jul;38(1):941-942.
- Isak B, Uluc K, Tanridag T, Ozsahin S, Dengler R, Us O, Petri S. Madras motor neuron disease in Turkey. Amyotrophic Lateral Sclerosis. 2009 Jan 1;10(5-6):347-349.
- Phanthumchinda K, Supcharoen O, Mitrabukdi E. Madras pattern of motor neuron disease: case report from Thailand. Journal of the Medical Association of Thailand. 1996 Jun 1;79(6):399-402.
- Shankar SK, Gourie-Devi M, Shankar L, Yasha TC, Santosh V, Das S. Pathology of Madras type of motor neuron disease (MMND)—a histological and immunohistochemical study. Acta Neuropathologica. 2000 Mar;99(4):428-434.
- Nalini A, Thennarasu K, Yamini BK, Shivashankar D, Krishna N. Madras motor neuron disease (MMND): clinical description and survival pattern of 116 patients from Southern India seen over 36 years (1971–2007). Journal of the Neurological Sciences. 2008 Jun 15;269(1-2):65-73.
- Meenakshisundaram E, Jagannathan K, Ramamurthi B. Clinical pattern of motor neuron disease seen in younger age groups in Madras. Neurology India. 1970.
- Nalini A, Pandraud A, Mok K, Houlden H. Madras motor neuron disease (MMND) is distinct from the riboflavin transporter genetic defects that cause Brown–Vialetto–Van Laere syndrome. Journal of the Neurological Sciences. 2013 Nov 15;334(1-2):119-122.
- Khan S, Rashid S. Madras motor neuron disease: Crossing borders. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2013 Apr 1;14(3):230-231.
