October 30th is Hypophosphatasia Awareness Day and because I was recently diagnosed with this ultra-rare genetic disease I wanted to write two posts. One to go into detail about the disease using current research, and the second post about my own journey with the disease and diagnosis.
Alkaline Phosphatase= ALP
Hypophosphatasia (HPP) is a rare progressive inherited (genetic) disease that is devastating to a lot of patients with debilitating systemic complications that can be life-threatening. It is an inborn error of metabolism with the hallmark biochemical feature of low serum alkaline phosphatase (ALP) activity (3). It occurs from what’s known in genetics as a loss of function mutation in the gene that encodes tissue-non-specific alkaline phosphatase. Which is just as it sounds, there’s a genetic mutation in the gene that encodes alkaline phosphatase making it nonfunctional in the body, which leads to very low ALP levels. With the low ALP levels, there is an increase in vitamin B6, calcium and other substrates that contribute to the disease presentation. The severity of the disease presentation is different for every patient.
There are two types of inheritance patterns in HPP: Autosomal Recessive and Autosomal Dominant. With HPP the autosomal recessive inheritance are the ones that tend to be lethal and most severe.
Autosomal Recessive: Have to inherit two mutated genes, usually one from each parent. Autosomal recessive gives a 25% chance of having a child who is unaffected and does not have the mutation, a 50% chance of having a child who carries the mutation, and a 25% chance of having a child who is affected and has the two mutated genes.
Autosomal Dominant: Only have to inherit one mutated gene. In autosomal dominant HPP each child has a 50% chance of inheriting the mutation.
HPP is not just a rare disease; it’s classified as Ultra-Rare. The estimation of HPP prevalence is about 1 of 100,000 people, which varies in some populations. It can be 1 out of 300,000 people and so on. In the UK the current estimate for severe HPP is about 7-8 new patients diagnosed per year.
Symptoms & Types of HPP:
People with HPP can experience many signs and symptoms: in bones like bowed legs, rachitic chest, bad joints; severely weakened muscles, teeth, and lungs; neurological issues like seizures; and kidney disease due to calcium build up on the kidneys. The symptoms occur due to the low level of ALP in the body allowing things like calcium, phosphate, & vitamin B6 to accumulate throughout the skeleton and organs.
Generally, you will hear of perinatal, infantile, childhood or adult Hypophosphatasia but there are a couple of more listed in the literature which i’ll break down here and the inheritance pattern.
❖ Perinatal Hypophosphatasia is almost always fatal as they often fail to even form a skeleton in utero. (autosomal recessive).
❖ Infantile Hypophosphatasia presents after birth but before 6-months and if fatal in about 50% of the infants (autosomal recessive).
❖ Childhood or Juvenile Hypophosphatasia presents after 6months but before adult and is moderate to severe leading to skeletal abnormalities, unmineralized bones, lung problems and more. (autosomal dominant or recessive).
❖ Benign Prenatal Hypophosphatasia is in between perinatal, infantile and childhood. Often can see skeletal abnormalities in utero then symptoms improve post birth that can be similar to infantile/childhood, adult or the mildest form odonto HPP.
❖ Adult Hypophosphatasia typically presents during middle age and includes osteomalacia or osteoporosis and metatarsal fractures. It can progress to be very debilitating (autosomal dominant).
❖ Odonto hypophosphatasia is the mildest form of the disease that has dental complications with premature teeth loss. Sometimes they do have evidence of osteomalacia or rickets and sometimes they do not. (autosomal dominant).
Why is Alkaline Phosphatase (ALP) important?
Alkaline Phosphatase is an enzyme that plays a very important role in bone formation. It is expressed abundantly in the skeleton, liver, and kidneys. When levels of ALP are normal it allows calcium and phosphate to work together and help form healthy mineralized bones.
Due to the genetic mutation in people with HPP that causes ALP to be extremely low and not really functional the calcium and phosphate cannot work together to build healthy bones and instead of them working together they start to build up in other places of the body leading to damage of the bones and organs. There are also specific substrates that build up in the body that ALP helps regulate and also accumulate in the body, which can be in the blood, urine, and organs.
Those substrates are inorganic pyrophosphate (PPi), pyridoxal 5′-phosphate (PLP) and phosphoethanolamine (PEA). These all contribute to the devastating effects of the disease.
Pyridoxal 5′-phosphate is the circulating form of vitamin B6 and in patients with HPP vitamin B6 is elevated because there is not enough alkaline phosphatase to keep the vitamin B6 regulated. This marker is also very sensitive and specific biochemical marker for HPP, given it’s elevated in the absence of any known vitamin B6 supplements and in conjunction with low ALP. If vitamin B6 is too high in the body it can cause its own set of symptoms, the most common in HPP being vitamin B6 dependent seizures.
Treatment and Outlook:
Treatment for HPP is complicated. Due to the underlying genetic cause of the disease and the way it affects the bones traditional osteoporosis medications cannot be used and have very little effect on bone strength in HPP patients and they can also make the disease worse. It was mostly aimed at managing the symptoms using pain management and surgical methods. In 2015 there was finally the first ever approved therapy for HPP. It’s an enzyme replacement drug called Strensiq. This therapy replaces the ALP in the body, which can help strengthen the bones and ease the symptoms of the disease. It is only approved for perinatal, infantile and childhood/juvenile forms of the disease and is highly regulated. Adults who are diagnosed later in life but who clearly showed symptoms as a child can get on it if you can prove they have always had symptoms before an adult. It’s not a one-drug fix all but it is improving the outlook of the disease for many patients.
Hypophosphatasia is much more than just a bone disease. It can be life-threatening and carries a lifelong impact on affected patients. Thankfully, with the treatment and early diagnosis, the outlook has gotten better.
The papers from Dr. Michael Whyte and the websites used for reference. Also, thank you to my friend Shelly Idziak, MD for her help.
Whyte, M. P. (2017). Hypophosphatasia: An overview For 2017. Bone,102, 15-25. doi:10.1016/j.bone.2017.02.011
Whyte, M. P., Zhang, F., Wenkert, D., Mcalister, W. H., Mack, K. E., Benigno, M. C., . . . Mumm, S. (2015). Hypophosphatasia: Validation and expansion of the clinical nosology for children from 25years experience with 173 pediatric patients. Bone,75, 229-239. doi:10.1016/j.bone.2015.02.022