Laurence-Moon syndrome (ORPHA:2377)
A very rare genetic multisystemic disorder characterized by progressive neurological, ophthalmologic and endocrine manifestations leading to severe handicap.
Epidemiology
The prevalence is unknown.
Clinical description
The neurological manifestations include peripheral neuropathy, spastic paraplegia and cerebellar ataxia. The symptoms progressively worsen for patients over time. The ophthalmologic manifestations are caused by chorioretinal dystrophy presenting widespread chorioretinal atrophy (thinning of the retina, loss of retinal architecture and choroid vessels) under fundus observation. The onset of visual impairment ranges widely from 1 year old to 60 years old. Hypogenitalism is present at birth due to hypogonadotrophic hypogonadism with primary amenorrhea, small penis and testes, or absence of pubic hair/breast development. Related growth delay during adolescence can also occur.
Etiology
Likely pathogenic or pathogenic variants in the PNPLA6 gene have been identified in patients with Laurence-Moon syndrome (LMS). The PNPLA6 gene codes for the patatin-like phospholipase domain-containing protein 6, also called neuropathy target esterase (NTE), a 1375 amino acids long protein (UniProt accession number: Q8IY17). The protein is composed of 5 domains including a single pass transmembrane domain (N-terminus), 3 cyclic nucleotide-binding domains (cNMP) and a NEST domain (NTE-esterase domain) at the C-terminus. The protein is a serine hydrolase that functions as a phospholipase B by catalyzing the deacylation of glycerophospholipids. It has also been shown to have a strong lysophospholipase activity. Altogether it plays a major role in phospholipid homeostasis, membrane trafficking, and axonal integrity in cells. Previously, the terms Laurence-Moon-Biedl syndrome or Laurence-Moon-Bardet-Biedl syndrome were used for this disease. However, the association Laurence-Moon/Bardet-Bield is no longer relevant given the different underlying gene mechanisms. It should be underlined that this condition is now clearly considered as part of the continuous spectrum of PNPLA6-related disorders linked to NTE activity. Recent evidence seems to inversely correlate the level of NTE activity with disease severity and tissue onset.
Diagnostic methods
Diagnosis is suspected on clinical presentation and confirmed by genetic testing including sequencing of the PNPLA6 gene (by direct Sanger sequencing or panel/exome next generation sequencing).
Differential diagnosis
The main differential diagnoses are the other PNPLA6-related disorders such as autosomal recessive spastic paraplegia type 39, cerebellar ataxia-hypogonadism syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome and trichomegaly-retina pigmentary degeneration-dwarfism syndrome that share all or a subset of the clinical manifestations, sometimes with a different age of onset.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant(s) have previously been identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment is only symptomatic and depends on the severity of the neurological manifestations. Optical aids can be provided to manage visual impairment.
Prognosis
Data on prognosis is limited for patients with PNPLA6-related disorders but recent evidence has shown a highly dependent relation between the NTE activity and severity of the disease and/or tissue onset.

                            Last update: 
                            April 2024


                            - Expert reviewer(s): 
                            Pr Hélène DOLLFUS | ERN-EYE* - Dr Jean MULLER | ERN-EYE*


                                * European Reference Network