Dear Editor,

We read with great interest the Letter by Di Rauso and colleagues [1]. The authors described an individual with adult-onset dystonia-parkinsonism with nigrostriatal denervation carrying a deletion of chromosome 18p encompassing GNAL (OMIM# 615073) and speculated that GNAL could play a significant role not only in dystonia but also in degenerative parkinsonism [1].

The phenotypes of chromosome 18p deletion syndrome [2,3] vary widely among individuals due to differences in the size of breakpoints and genes involved in the deletion [3] and may include generalized dystonia and tremor [4].

Here, we highlight our experience with the heterogeneous phenotypic presentation of 18p syndrome by reporting two unrelated patients who presented with vigorous tremulous dystonia associated with monosomy 18p [5] that caused protein subunit alpha L (GNAL) gene [6] haploinsufficiency. A detailed map of the deleted 18p regions obtained by array-comparative genomic hybridization (aCGH) is also provided for both patients (Figure 1).

Patient 1 (P1) was a 67-year-old man who presented with neurological manifestations characterized by adult-onset generalized dystonia involving the face, larynx, upper limbs, and right lower limb and subsequently developed slight hypokinesia (Supplementary Video 1 in the online-only Data Supplement). After age 40, he manifested progressive jerky tremors of the upper limbs (more severe in the right hand, with the additional development of mild rest tremors), and tremulous voice dystonia developed at the age of 54 after cholecystectomy. He later developed eyelid dystonia (apraxia of lid opening). His gait was characterized by mild action-dystonia of the right lower limb. Brain magnetic resonance imaging (MRI) revealed a slight T2-weighted hyperintensity of the left internal pallidum (Figure 1), while the DaT (I-123 ioflupane) scan suggested normal presynaptic dopaminergic terminals. The patient’s response to levodopa was limited to a moderate benefit for limb hypokinesia/clumsiness. The nonneurological clinical manifestations were typical of 18p deletion syndrome and included short stature, craniofacial dysmorphism (triangular face with mid-hypoplasia, low-set ears, and bilateral eyelid ptosis), moderate intellectual disability, autoimmune thyroiditis, and pernicious anemia. A neuropsychological evaluation at age 58 confirmed the presence of moderate mental retardation (global Wechsler Adult Intelligence ScaleRevised score of 62 with a verbal score of 62 and a performance score of 68). Genetic analysis revealed a deletion of 13.33–13.37 Mb in the 18p11.32p11.21region: arr[hg19] 18p11.32p11.2 (118729x2, 118788_1346377x1,13496784x2) (Figure 1, P1).

Patient 2 (P2) was a 59-year-old woman who presented with neurological manifestations characterized by multifocal adult-onset dystonia, which started in the left leg (thigh flexion) and progressed to the left arm with cervical and laryngeal (vocal cord hyperadduction) involvement; the laryngeal involvement caused mild dysphagia. Since the age of 33, her gait stability was severely affected (Supplementary Video 1 in the online-only Data Supplement). She was treated with botulinum toxin injections in the left upper limb (in the biceps, brachioradialis and radial extensor carpi), to which she showed a good response for many years. A brain MRI scan performed due to behavioral alterations (psychomotor agitation due to hallucinations) demonstrated marked diffuse cerebellar atrophy and chronic vascular encephalopathy. Her syndromic features included severe intellectual disability (intelligence quotient 47), short stature, short webbed neck, microcephaly, and bilateral eyelid ptosis [7] treated with blepharoplasty. Genetic analysis revealed a deletion of 14.19–14.22 Mb in the 18p11.32p11.21region: arr[hg19] 18p11.32p11.21 (14275_14206245x1,14220801x2) (Figure 1, P2).

Our study significantly expands the complex phenotypic spectrum of GNAL haploinsufficiency caused by 18p deletion [8]. P1 developed clumsiness and slow hand movements resembling mild hypokinesia at a later point in a very long follow-up period (more than 15 years after onset); in contrast to the patient reported by Di Rauso et al. [1], our patient had a normal DaT scan. Moreover, both reports support the concept of extensive clinical diversity and different motor circuitry involvement in 18p syndrome patients [3-5,7,9].

The brain MRI of P1 revealed left globus pallidus internus (GPi) hyperintensity; this finding was not previously described, and it is possible that these alterations may be aspecific and that an acquired left GPi lesion may have worsened the dystonic tremor of the right limb in our patient. The brain MRI of P2 revealed marked diffuse cerebellar atrophy, which is a unique finding not previously reported in patients affected by 18p deletion syndrome. The pathogenesis of cerebellar involvement is not clear. One possibility is that this finding may be related to dysfunction of the LAMA1 gene (deleted in both patients), which plays a role in the development of the cerebellum; therefore, mutations of this gene may be associated with cerebellar ataxia [10]. On the other hand, the long-term disease course and the possible evolution of brain imaging in patients with 18p deletion syndrome are not well known; therefore, some characteristics may have not been reported to date, as the literature includes only cross-sectional studies.

In conclusion, there are important practical implications for diagnostics based on the lessons learned from these studies. We suggest that GNAL haploinsufficiency should also be suspected in tremulous dystonia patients with or without combined hypokinesia/akinesia when the phenotype of 18p deletion syndrome is observed [3] independently from dopaminergic system image results. In addition, we recommend that aCGH analysis should be performed to identify chromosomal breakpoints and deleted genes; however, when aCGH analysis is not available, diagnostic technologies such as next-generation sequencing for hyperkinetic disorders or a whole-exome sequencing read-depth-based algorithm [9] should be used.

Supplementary Materials

Video 1.

Segment 1: The patient presented with mild dysarthria, severe dystonic jerky tremors (more severe in the right hand), clumsiness/hypokinesia of the limb movements, and task-specific right lower limb dystonia during gait. Captions are embedded into the video. Segment 2: The patient had multifocal dystonia, prevalent on the left side of the body with cranial (oromandibular, eyelids), cervical (retrocollis), and laryngeal involvement; her gait was marked by axial and lower limb dystonia. Captions are embedded into the video.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author Contributions

Conceptualization: Arianna Braccia, Miryam Carecchio, Luigi Michele Romito. Data curation: all authors. Investigation: all authors. Methodology: Miryam Carecchio, Francesca Luisa Sciacca, Anna Castagna, Antonio Emanuele Elia, Luigi Michele Romito. Project administration: Miryam Carecchio, Luigi Michele Romito. Visualization: Arianna Braccia, Miryam Carecchio, Luigi Michele Romito. Writing—original draft: Arianna Braccia, Miryam Carecchio, Anna Castagna, Antonio Emanuele Elia, Luigi Michele Romito. Writing—review & editing: all authors.

Acknowledgments

We would like to thank our patients and their relatives who permitted us to acquire thewhole medical documentation and who gave permission to publish this manuscript and the videos.

Figure 1.

Neuroimaging findings, chromosomal breakpoints from array-CGH analysis, and protein-coding genes in the deleted region of the two patients. P1, patient 1; P2, patient 2; M, male; F, female; CGH, comparative genomic hybridization; GPi, globus pallidus internus; T2wMRI, T2 weighted magnetic resonance imaging; T1/PDwMRI, T1/PD weighted magnetic resonance imaging; PD, Parkinson’s disease.

REFERENCES

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