Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

doi:10.21203/rs.3.rs-2485442/v1

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Case Report

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

https://doi.org/10.21203/rs.3.rs-2485442/v1

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published 27 Apr, 2023

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Background:

Neutral lipid storage disease with myopathy (NLSD-M) is an autosomal recessive disease that manifests itself around the 3rd to 4th decade with chronic myopathy of proximal predominance in the shoulder girdle. Clinical myotonia is uncommon. We will report a rare case associated with pathogenic mutations on PNPLA2 and CLCN1 genes with a mixed phenotype of NLSD-M and a subclinical form of Thomsen’s congenital myotonia.

Case presentation:

We describe a patient with chronic proximal myopathy, very subtle clinical myotonia and electrical myotonia on electromyography (EMG). Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL). A blood smear analysis showed Jordan’s anomaly, a hallmark of NLSD-M. A genetic panel was collected using the NGS technique, which identified two pathogenic variants on genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia, whose association has not been previously described.

Conclusions:

Although uncommon, it is important to remember the possibility of association of pathogenic mutations to explain a specific neuromuscular disease phenotype. The use of a range complementary methods, including myopathy genetic panels, may be essential to diagnostic definition in such cases.

Neutral lipid storage disease with myopathy

Thomsen’s congenital myotonia

myopathy

myotonia

Jordan’s anomaly

PNPLA2

CLCN1

Neutral lipid storage disease with myopathy (NLSD-M) is a rare autosomal recessive disease [1, 2] caused by mutations in the Patatin Like Phospholipase Domain Containing 2 (PNPLA2) gene which encodes adipose triglyceride lipase (ATGL). This enzyme participates of the intracellular triglyceride hydrolysis in the cellular cytoplasm thus a complete or partial loss of the enzymatic activity affects the energetic metabolism leading to intracellular accumulation of lipid vacuoles containing triacylglycerol (TAG) and cell damage [1, 3, 4].

Clinical findings of NLSD-M are related to impairment of striated skeletal and cardiac musculature [5]. The typical age of symptoms onset is in the second or third decade, starting with slow progressive proximal limb weakness and atrophy, especially in shoulder girdle (70% of the cases) [6], although less pronounced pelvic girdle and distal musculature involvement are commonly present [6]. Cardiac pathology can occur lately in half of patients, usually observed in the fourth decade of life [6]. Hepatomegaly, diabetes mellitus and hypertriglyceridemia can also occur [7, 8]. In contrast, orofacial and ocular musculature dysfunction, dysphagia, and respiratory failure are usually absent.

Pathogenic mutations on CLCN1 gene are associated to congenital myotonia and the pattern of genetic inheritance can be autosomal recessive (eg. Becker disease) or autosomal dominant (eg. Thomsen disease). The hallmark of these conditions is the myotonic phenomenon, a delayed relaxation of skeletal muscles after voluntary contraction, that can be associated with painful muscle cramps, muscle hypertrophy and proximal weakness. Becker disease presents with late-onset symptoms, moderate to severe myotonia and transient proximal muscle weakness that can become permanent. On the other hand, Thomsen disease has an earlier onset, with mild symptoms and permanent muscle weakness is usually absent. Furthermore, mutations related to Thomsen disease have reduced penetrance and variable phenotype presentation [9].

Here, we describe a patient with chronic proximal myopathy, very subtle clinical myotonia and electrical myotonia on electromyography (EMG) related to both pathogenic mutations on PNPLA2 and CLCN1 genes. This association of NLSD-M and a subclinical form of Thomsen’s congenital myotonia not previously described was made through clinical, electromyographic and genetic findings coexisting in the same patient.

A 42 years-old female patient admitted to a reference center for Neuromuscular Disorders in northeastern of Brazil with a 7 year history of progressive proximal upper limbs weakness. Five years after symptoms onset she also noticed mild proximal lower limbs and distal upper limbs weakness associated to proximal muscle atrophy, specially of shoulder girdle. Strenuous exercise and cold exposure induces myalgia and worsening of weakness.

There were no complains of fluctuating symptoms, diplopia, eyelid ptosis, dysphagia, dysphonia, dysarthria, dyspnea or abnormal urine color. Past medical history was negative for other conditions as well as substances abuse. Family health history was also negative for neuromuscular diseases.

Clinical evaluation confirmed proximal weakness of four limbs, moderate on pelvic girdle and severe on shoulder girdle with atrophy and very subtle handgrip myotonia. Fasciculations, joint contractures or sensory impairment were not present. Deep tendon reflexes were globally reduced.

Serum laboratory analysis disclosure hyperCKemia (CK 1280 mg/dL) and excluded others abnormalities (electrolytes disturbance, thyroid, kidney and liver disfunction), infectious diseases (retrovirus, syphilis, hepatitis B and C) and serum biomarkers of collagenosis or inflammatory myopathies. Serum protein electrophoresis was normal.

Nerve conduction studies (NCS) and needle EMG were performed, which showed normal motor and sensory nerve conduction parameters and myopathic pattern: increased and early motor recruitment, decreased duration and amplitude of motor unit potentials (MUP) with short polyphasic potentials. The EMG abnormalities were more evident on proximal upper limbs muscles and with a mosaic pattern (myopathic/normal) on lower limbs muscles. Furthermore, signs of membrane instability (fibrillations and positive sharp waves) were identified on upper and lower limbs and paravertebral musculature as well as electrical myotonia in some muscles (Fig. 1). Slow repetitive nerve conduction study was normal.

Patient underwent a whole-body 1,5 Tesla magnetic resonance image to access the pattern of muscles impairment. Atrophy degree was measured using modified Mercuri scale by Fischer et al, 2008 [10] – Fig. 2. Then, we found the following pattern of atrophy: soleus, medial head of gastrocnemius and posterior tibialis (grade 2), semimembranosus and long head of biceps femoris (grade 2), gluteus minimus (grade 4), gluteus maximus (grade 3), deltoid (grade 2), biceps brachii and brachii (grade 4), supraspinatus and infraspinatus (grade 4). It showed also a hyperintense signal on STIR sequence involving soleus, medial head of the gastrocnemius and posterior tibial, showing signs of muscle edema.

Given the initial suspicion of inherited metabolic myopathy, a genetic panel was collected using the NGS technique, which identified two pathogenic variants on Gene NM_020376.4(PNPLA2):c.792del(p.Leu264fs) and NM_000083.3(CLCN1):c.14.53A > G(p.Met485Val) genes supporting two different diagnosis: NLSD-M and Thomsen congenital myotonia. Peripheral blood smear analysis showed as Jordan’s anomaly (Fig. 3), a hallmark of NLSD-M.

We also performed a multisystemic evaluation with electrocardiogram, transthoracic echocardiogram, abdominal ultrasound, ophthalmological evaluation and lipid and glycemic profile that were normal.

This case report presents a unique case of an association NLSD-M and a subclinical form of Thomsen’s congenital myotonia, with no other similar case reported in literature for our knowledgment. Initially, the suspicion of a genetic etiology for this condition arose due to the chronic and progressive course of proximal myopathy without an obvious secondary acquired cause. Is important to notice that a negative familial history does not put away a genetically based etiology, especially due the possibility of a de novo mutation, incomplete inheritance and lack of information about the actual degree of kinship between family members.

In the presence of paravertebral myotonia and exercise intolerance is essential to exclude metabolic myopathies, mainly Pompe disease and myotonic dystrophy type 2 as possible etiologies. However, this case report shows other important differential diagnosis of metabolic myopathy: NLSD-M, in which an asymmetric weakness more evident on shoulder girdle raises suspicion. A hallmark of this condition that is present on 100% of cases is the presence of triacylglycerol (TAG) vacuoles in leukocytes cytoplasm evident on peripheral blood smear, denominated Jordan’s anomaly [11, 12]. Thus, this simple laboratory test can be used as a screening evaluation for young patients with isolated hyperCKemia, aiming for an early diagnosis of NLSD-M [11, 12].

In this case, we found two rare pathogenic mutations in the same patient that explained all the clinical and EMG findings. Thus, although uncommon, it is important to remember the possibility of association of pathogenic variants to justify a specific neuromuscular disease phenotype. A broad genetic panel evaluation was essential for diagnostic definition, therapeutic decision, prognostic evaluation and genetic counseling in this case.

NLSD-M

Neutral lipid storage disease with myopathy

PNPLA2

Patatin Like Phospholipase Domain Containing 2

ATGL

adipose triglyceride lipase

TAG

vacuoles containing triacylglycerol

EMG

electromyography

NCS

Nerve conduction studies

MUP

motor unit potentials

Ethics approval and consent to participate:

The ethics committee 5040 - Hospital Geral de Fortaleza - HGF/SUS, approved the study with reference number 64841922.4.0000.5040.

Consent for publication:

Written informed consent was obtained from the patient for publication of this case and any accompanying images.

Availability of data and materials:

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests:

The authors declare that they have no competing interests.

Funding:

We received no funding for this study.

Authors' contributions:

JIDL, EBO, ISR, LAB, HCF, IHMM, DGFT: Literature review, preparation, review, editing and formatting of original draft;

CLR: Supervision, Review and Formatting; Conceptualization, Methodology.

All authors read and approved the final manuscript.

Acknowledgements:

Not applicable;

Authors' information:

Not applicable;

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No competing interests reported.

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Journal Publication

published 27 Apr, 2023

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Editorial decision: Major revision
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Reviewers agreed at journal
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31 Jan, 2023
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Editor invited by journal
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Submission checks completed at journal
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You are reading this latest preprint version

Neutral lipid storage disease with myopathy and myotonia associated to pathogenic variants on PNPLA2 and CLCN1 genes: case report.

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Background:

Case presentation:

Conclusions:

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