Claudia Castiglioni

PRRT2 mutation causes paroxysmal kinesigenic dyskinesia and hemiplegic migraine in monozygotic twins

PRRT2 gene mutations have recently been identified as a causative gene of Paroxysmal kinesigenic dyskinesia (PKD), a rare movement disorder characterised by the occurrence of chorea, dystonia or athetosis triggered by sudden action. Some patients have additional intermittent neurologic disorders like infantile convulsions. The association with migraine has been rarely reported in this condition. Here we report the coexistence of PKD and hemiplegic migraine in twins harbouring a heterozygous mutation in PRRT2. Two monozygotic twins manifesting PKD together with repeated episodes of migraine with some severe attacks of hemiplegic migraine have been followed and treated for more than 10 years. Molecular genetic analysis disclosed the c.649_650insC, p.R217Pfs*8 heterozygous mutation in both twins. This mutation was segregating from the mother who likewise harboured the same mutation c.649dupC although she had never manifested PKD but complained of rare common migraine attacks in her past history. The association of PKD and hemiplegic migraine has been previously reported in one large family, associated to febrile convulsions and afebrile seizures in some individuals, but our report relates this association of symptoms to a mutation in PRRT2. The co-occurrence of both hemiplegic migraine and PKD in monozygotic twins expands the phenotypic spectrum of intermittent manifestations related to PRRT2 and perhaps suggests an additional causing gene for hemiplegic migraine.

Activating PIK3CA somatic mutation in congenital unilateral isolated muscle overgrowth of the upper extremity

Congenital unilateral overgrowth of the upper extremity affecting only the muscle tissue is rare. We describe on the clinical, histopathological, and neuroimaging findings in a 6‐year‐old girl with a congenital, non‐progressive muscle enlargement of the entire left upper limb with an ipsilateral hand deformity. No cutaneous stigmata or additional features were detected. Sanger sequencing for the AKT1, PIK3CA, and PTEN genes identified an activating c.3140A>G, p.H1047R mutation in the PIK3CA gene from the affected muscle DNA. We demonstrate that isolated congenital muscular upper limb overgrowth with aberrant hand muscles is another condition related genetically to the PIK3CA‐related overgrowth spectrum.

Toward an objective measure of functional disability in dysferlinopathy.

Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a cohort of patients with dysferlinopathy, using validated scales.

Muscle magnetic resonance imaging and histopathology in ACTA1‐related congenital nemaline myopathy

Introduction: Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. Methods: We assessed the clinical, histopathological, MRI, and molecular findings in a 19‐year‐old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. Results: Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. Conclusions: We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1‐related NM. Muscle Nerve 50: 1011–1016, 2014

Broadening the imaging phenotype of dysferlinopathy at different disease stages

MRI characterization of dysferlinopathy has been mostly limited to the lower limbs. We aimed to broaden the MRI description of dysferlinopathy and to correlate it with objective measures of motor dysfunction. Methods: Sequential whole‐body axial MRI was performed in 27 patients with genetically confirmed dysferlinopathy classified according to disease duration. Spearman correlations of fatty infiltration scores versus Motor Function Measure (MFM) were calculated. Results: Significant fatty infiltration was symmetrically present in early stages mainly in the posterior compartments of legs and thighs, thigh adductors, pelvic girdle, and some paravertebral muscles and the subscapularis. Later, fatty infiltration involved leg and thigh anterior compartments, arms and forearms, paravertebral, and trunk muscles. MRI infiltration score correlated positively with disease duration and negatively with MFM scale. Conclusions: We expand MRI characterization of dysferlinopathy and provide evidence for use of MRI scoring combined with motor functional scales to assess the natural course of disease. Muscle Nerve, 2016 Muscle Nerve 54: 203–210, 2016

Neuromyopathy with congenital cataracts and glaucoma: a distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy.