Spastic Paraplegia 28 via the DDHD1 Gene

Spastic Paraplegia 28 (SPG28) is a type of hereditary spastic paraplegia (HSP) characterized by early-onset, slow and progressive weakness and spasticity of the lower limbs. A few cases with mild upper limb involvement have also been reported (Bouslam et al. 2005; Liguori et al. 2014; Mignarri et al. 2016; Miura et al. 2016). Some patients with SPG28 may also show distal sensory loss, axonal neuropathy and cerebellar eye movement disturbances (Bouslam et al. 2005; Tesson et al. 2012). Severity of symptoms and rate of progression are quite variable.

The transmission of disease in the families with SPG28 is consistent with autosomal recessive inheritance. Bouslam et al. (2005) mapped this disease to DDHD1 (DDHD-domain-containing 1), which belongs to the intracellular phospholipase A1 gene family and encodes phosphatidic acid-preferring phospholipase A1 (PA-PLA1). Following cell activation, phosphatidic acid is released and functions as a second messenger in several signaling pathways. PA-PLA1 is a lipase that catalyzes degradation of phosphatidic acid and attenuates cell activation (Higgs et al. 1998). PA-PLA1 is involved in the maintenance of the Golgi and ER structure, and regulation of mitochondrial dynamics. Pathogenic variants in DDHD1 may cause mitochondrial dysfunctions that result from the accumulation of phosphatidic acid (Higgs et al. 1998; Nakajima et al. 2002). To date, nonsense, splice, and small deletions/duplications have been identified in DDHD1 (Human Gene Mutation Database).

It is difficult to estimate the clinical sensitivity of this test due to the lack of large cohort studies. All the pathogenic variants reported to date in DDHD1 are detectable by sequencing.

This test provides full coverage of all coding exons of the DDHD1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).