Objective: To report the clinical and genetic evaluation of a five-generation family with eight members exhibiting moaning.

Background: Moaning is characterized by low-tone abnormal involuntary, purposeless and inappropriate phonations. It has been described in patients with Parkinson’s disease (PD)1 and atypical parkinsonism2 and is occasionally associated with pain or the use of levodopa3. Heterozygous mutations in the NEFH gene are responsible for axonal Charcot-Marie-Tooth disease type 2CC. To date, there was no prior association between moaning and variants in this gene.

Method: Neurologic examinations were conducted on the index patient and five relatives, including a total of four affected. Exome sequencing was used in three affected family members to identify rare, protein-changing variants shared by all three family members. Sanger sequencing was used to validate six candidate variants for segregation in all six available family members.

Results: Moaning was reported in eight members in five generation in this family. The proband had mild PD without cognitive impairment and showed excellent response to levodopa. Moaning appeared more than 20 years prior to the PD diagnosis. Her deceased mother and grandfather, as well as three sons, one daughter and one grandchild also had moaning for several years. None of them had PD or any other neurological disorder. Moaning in all affected members occurred intermittently at variable daily frequency, lasted many seconds and was not related to pain. The proband and her affected daughter had normal electromyography and nerve conduction studies. A rare, heterozygous variant (c.735C>G, p.Ile245Met) was found in NEFH, in all available affected but in none of the unaffected family members. This variant was the best candidate based on stringent filtering criteria including in-silico prediction and expression pattern. There was no neuropathy in the proband.

Conclusion: The members of this family affected with moaning carried a variant in NEFH in the absence of neuropathy. If the variant is linked to the moaning remains elusive. Alternatively to a genetic cause, moaning may be considered as a type of stereotype and explained by an over-learning process as described for tics or echopraxia of stereotypes. Finally, a functional cause of moaning in this family cannot be ruled out. Further genetic studies in individuals with moaning are warranted.

References: [1] Lim SY, Tan AH, Lim JL, Ahmad-Annuar A. Purposeless Groaning in Parkinson’s Disease. J Mov Disord. 2018;11:87-88. [2] Stamelou M, Rubio-Agusti I, Quinn N, Bhatia K. Characteristic constant groaning in late stage progressive supranuclear palsy: a case report. Parkinsonism Relat Disord. 2011;17:575–576. [3] Ishii K, Kumada M, Ueki A, Yamamoto M, Hirose H. Involuntary expiratory phonation as a dose-related consequence of L-dopa therapy in a patient with Parkinson’s disease. Ann Otol Rhinol Laryngol. 2003;112:1040-1042.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/moaning-genetic-analysis-of-a-family-with-eight-affected-members/