Volume 23, Issue 10 pp. 1580-1587
Original Article

Identification of mutations in AP4S1/SPG52 through next generation sequencing in three families

A. Tessa

A. Tessa

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy

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R. Battini

R. Battini

Child Neurology, IRCCS Stella Maris, Pisa, Italy

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A. Rubegni

A. Rubegni

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy

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E. Storti

E. Storti

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy

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C. Marini

C. Marini

Pediatric Neurology Unit, Children's Hospital ‘A. Meyer’, University of Florence, Florence, Italy

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D. Galatolo

D. Galatolo

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy

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R. Pasquariello

R. Pasquariello

Neuroradiology, IRCCS Stella Maris, Pisa, Italy

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F. M. Santorelli

Corresponding Author

F. M. Santorelli

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy

Child Neurology, IRCCS Stella Maris, Pisa, Italy

Correspondence: F. M. Santorelli, IRCCS Stella Maris, via dei Giacinti 2, 56128 Pisa, Italy (tel.: +39 050886275; fax: +39 050886247; e-mail: [email protected]).Search for more papers by this author
First published: 22 July 2016
Citations: 34

Abstract

Background and purpose

The term hereditary spastic paraplegia (HSP) covers a spectrum of genetically heterogeneous disorders in which lower limb spasticity is the common clinical feature. Many patients with childhood-onset HSP are mistakenly diagnosed with cerebral palsy (CP).

Methods

A group of as yet molecularly undiagnosed HSP patients were analyzed using SpastoPlex, a customized target re-sequencing panel able to investigate the coding regions of 72 genes linked to HSP, spastic ataxias or related motor diseases.

Results

Our investigations identified loss-of-function mutations in AP4S1/SPG52 in four children (three families) who had previously received a diagnosis of diplegic/quadriplegic CP. The patients presented spastic paraparesis, mild facial dysmorphisms, moderate-to-severe intellectual disability and severe speech delay. Two patients manifested febrile seizures and childhood-onset focal seizures. In all the patients, brain magnetic resonance imaging (MRI) showed a peculiar hypoplastic posterior corpus callosum, often associated with ventriculomegaly, white matter loss and cerebral atrophy.

Conclusion

Adaptor protein 4 (AP-4) deficiency disorders should be suspected in children with spastic paraparesis, cognitive deficit and absent speech accompanied by suggestive MRI features. Seizures might be amongst the clinical manifestations of the syndrome.

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